δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides

ABSTRACT

δ-Amino-γ-hydroxy-ω-aryl-alkanoic acid amides of formula I ##STR1## and the salts thereof, have renin-inhibiting properties and can be used as antihypertensive medicinal active ingredients.

The invention relates to novel δ-amino-γ-hydroxy-ω-aryl-alkanoic acidamides of formula I ##STR2## wherein R₁ is hydrogen, hydroxy, loweralkoxy, cycloalkoxy, lower alkoxy-lower alkoxy or free or esterified oramidareal carboxy-lower alkoxy,

R₂ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy-lower alkyl, loweralkoxy-lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy,optionally lower alkanoylated, halogenated or sulfonylated hydroxy-loweralkoxy; amino-lower alkyl that is unsubstituted or substituted by loweralkyl, by lower alkanoyl and/or by lower alkoxycarbonyl; optionallyhydrogenated heteroaryl-lower alkyl; amino-lower alkoxy that issubstituted by lower alkyl, by lower alkanoyl and/or by loweralkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, cycloalkoxy, loweralkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkoxy, loweralkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-loweralkenyloxy, lower alkenyloxy-lower alkyl, lower alkanoyl-lower alkoxy,optionally S-oxidised lower alkylthio-lower alkoxy, loweralkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, cyano-lower alkoxy, free oresterified or amidated carboxy-lower alkoxy or free or esterified oramidated carboxy-lower alkyl,

R₃ is optionally halogenated lower alkyl, lower alkoxy-lower alkyl,cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally S-oxidisedlower alkylthio-lower alkyl, optionally hydrogenarealheteroarylthio-lower alkyl, optionally hydrogenated heteroaryl-loweralkyl; amino-lower alkyl that is unsubstituted or N-mono- orN,N-di-lower alkylated, N-lower alkanoylated or N-loweralkanesulfonylated or N,N-disubstituted by lower alkylene, byunsubstituted or N'-lower alkylated or N'-lower alkanoylated aza-loweralkylene, by oxa-lower alkylene or by optionally S-oxidised thia-loweralkylene; cyano-lower alkyl, free or esterified or amidatedcarboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy,cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy,hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated loweralkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally hydrogenatedheteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted orN-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-loweralkanesulfonylated or substituted by lower alkylene, by unsubstituted orN'-lower alkylated or N'-lower alkanoylated aza-lower alkylene, byoxa-lower alkylene or by optionally S-oxidised thia-lower alkylene;cyano-lower alkoxy or free or esterified or amidated carboxy loweralkoxy, or together with R₄ is lower alkylenedioxy or a fused-on benzoor cyclohexeno ring,

R₄ together with R₃ is lower alkylenedioxy or a fused-on benzo orcyclohexeno ring, or is hydrogen, lower alkyl, hydroxy, lower alkoxy orcycloalkoxy,

X is methylene or hydroxymethylene,

R₅ is lower alkyl or cycloalkyl,

R₆ is unsubstituted or N-mono- or N,N-di-lower alkylated or N-loweralkanoylated amino,

R₇ is lower alkyl, lower alkenyl, cycloalkyl or aryl-lower alkyl, and

R₈ is lower alkyl, cycloalkyl, free or aliphatically esterideal oretherideal hydroxy-lower alkyl; amino-lower alkyl that is unsubstitutedor N-lower alkanoylated or N-mono- or N,N-di-lower alkylated orN,N-disubstituted by lower alkylene, by hydroxy-, lower alkoxy- or loweralkanoyloxy-lower alkylene, by unsubstituted or N'-lower alkanoylated orN'-lower alkylated aza-lower alkylene, by oxa-lower alkylene or byoptionally S-oxidised thia-lower alkylene; free or esterified oramidated carboxy-lower alkyl, free or esterified or amidateddicarboxy-lower alkyl, free or esterideal or amidatedcarboxy-(hydroxy)-lower alkyl, free or esterified or amidatedcarboxycycloalkyl-lower alkyl, cyano-lower alkyl, loweralkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-loweralkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- orN,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radicalbonded via a carbon atom and optionally hydrogenated and/oroxo-substituted, or lower alkyl substituted by a heteroaryl radicalbonded via a carbon atom and optionally hydrogenated and/oroxo-substituted,

and to the salts thereof, to processes for the preparation of thecompounds according to the invention, to pharmaceutical compositionscontaining them, and to their use as medicinal active ingredients.

Aryl and aryl in aryl-lower alkoxy, aryl-lower alkyl and the like is,for example, phenyl or naphthyl that is unsubstituted or mono-, di- ortri-substituted by lower alkyl, lower alkoxy, hydroxy, lower alkylamino,di-lower alkylamino, halogen and/or by trifluoromethyl.

Cycloalkoxy and cycloalkoxy in cycloalkoxy-lower alkoxy is, for example,3- to 8-membered, preferably 3-, 5- or 6-membered, cycloalkoxy, such ascyclopropyloxy, cyclopentyloxy, cyclohexyloxy, also cyclobutyloxy,cycloheptyloxy or cyclooctyloxy.

Cycloalkyl is, for example, 3- to 8-membered, preferably 3-, 5- or6-membered, cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl,also cyclobutyl, cycloheptyl or cyclooctyl.

Free or esterified or amidated carboxy-lower alkoxy is, for example,carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-loweralkoxy or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy.

Optionally lower alkanoylated, halogenated or sulfonylated hydroxy-loweralkoxy is, for example, lower alkanoyloxy-lower alkyl, hydroxy-loweralkoxy, halo-(hydroxy)-lower alkoxy or loweralkanesulfonyl-(hydroxy)-lower alkoxy.

Amino-lower alkyl that is unsubstituted or substituted by lower alkyl,lower alkanoyl and/or by lower alkoxycarbonyl is, for example,amino-lower alkyl, lower alkylamino-lower alkyl, di-loweralkylamino-lower alkyl, lower alkanoylamino-lower alkyl or loweralkoxycarbonylamino-lower alkyl.

Amino-lower alkoxy that is unsubstituted or substituted by lower alkyl,lower alkanoyl and/or by lower alkoxycarbonyl is, for example,amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy or loweralkoxycarbonylamino-lower alkoxy.

Optionally S-oxidised lower alkylthio-lower alkoxy is, for example,lower alkylthio-lower alkoxy or lower alkanesulfonyl-lower alkoxy.

Optionally hydrogenated heteroaryl-lower alkoxy is, for example,optionally partially hydrogenated or N-oxidised pyridyl-lower alkoxy,thiazolyl-lower alkoxy or especially morpholino-lower alkoxy.

Optionally hydrogenated heteroarylthio-lower alkoxy is, for example,optionally partially or fully hydrogenareal heteroarylthio-lower alkoxy,such as thiazolylthio-lower alkoxy or thiazolinylthio-lower alkoxy,imidazolylthio-lower alkoxy, optionally N-oxidised pyridlylthio-loweralkoxy or pyrimidinylthio-lower alkoxy.

Free or esterified or amidated carboxy-lower alkyl is, for example,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-loweralkyl or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl.

Optionally halogenated lower alkyl is, for example, lower alkyl orpolyhalo-lower alkyl.

Optionally halogenated lower alkoxy is, for example, lower alkoxy orpolyhalo-lower alkoxy.

Optionally S-oxidised lower alkylthio-lower alkyl is, for example, loweralkylthio-lower alkyl or lower alkanesulfonyl-lower alkyl.

Optionally S-oxidised lower alkylthio-lower alkoxy is, for example,lower alkylthio-lower alkoxy or lower alkanesulfonyl-lower alkoxy.

Optionally hydrogenated heteroaryl-lower alkyl is, for example,optionally partially hydrogenated or N-oxidised pyridyl-lower alkyl.

Optionally hydrogenated heteroarylthio-lower alkyl is, for example,thiazolylthio-lower alkyl or thiazolinylthio-lower alkyl,imidazolylthio-lower alkyl, optionally N-oxidised pyridylthio-loweralkyl or pyrimidinylthio-lower alkyl.

Amino-lower alkyl that is unsubstituted or N-mono- or N,N-di-loweralkylated, N-lower alkanoylated or N-lower alkanesulfonylated orN,N-disubstituted by lower alkylene, by unsubstituted or N'-loweralkylated or N'-lower alkanoylated aza-lower alkylene, by oxa-loweralkylene or by optionally S-oxidised thia-lower alkylene is, forexample, amino-lower alkyl, lower alkylamino-lower alkyl, di-loweralkylamino-lower alkyl, lower alkanoylamino-lower alkyl, loweralkanesulfonylamino-lower alkyl, polyhalo-loweralkanesulfonylamino-lower alkyl, pyrrolidino-lower alkyl,piperidino-lower alkyl, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkyl, morpholino-lower alkyl,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothiomorpholino-loweralkyl.

Optionally S-oxidised lower alkylthio-lower alkoxy is, for example,lower alkylthio-lower alkoxy or lower alkanesulfonyl-lower alkoxy.

Amino-lower alkoxy that is unsubstituted or N-mono- or N,N-di-loweralkylated, N-lower alkanoylated or N-lower alkanesulfonylated orN,N-disubstituted by lower alkylene, by unsubstituted or N'-loweralkylated or N'-lower alkanoylated aza-lower alkylene, by oxa-loweralkylene or by optionally S-oxidised thia-lower alkylene is, forexample, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkanesulfonylamino-lower alkoxy, polyhalo-loweralkanesulfonylamino-lower alkoxy, pyrrolidino-lower alkoxy,piperidino-lower alkoxy, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkoxy, morpholino-lower alkoxy,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothio-morpholino-loweralkoxy.

Unsubstituted or N-mono- or N,N-di-lower alkylated or N-loweralkanoylated amino is, for example, amino, lower alkylamino, di-loweralkylamino or lower alkanoylamino.

Free or aliphatically esterified or etherified hydroxy-lower alkyl is,for example, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, loweralkoxy-lower alkyl or lower alkenyloxy-lower alkyl.

Amino-lower alkyl that is unsubstituted or N-lower alkanoylated, N-mono-or N,N-di-lower alkylated or N,N-disubstituted by lower alkylene, byhydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, byunsubstituted or N'-lower alkanoylated aza-lower alkylene, by oxa-loweralkylene or by optionally S-oxidised thia-lower alkylene is, forexample, amino-lower alkyl, lower alkanoylamino-lower alkyl, N-mono- orN,N-di-lower alkylamino-lower alkyl, optionally hydroxylated or loweralkoxylated piperidino-lower alkyl, such as piperidino-lower alkyl,hydroxypiperidino-lower alkyl or lower alkoxy-piperidino-lower alkyl,piperazino-, W-lower alkylpiperazino- or N'-loweralkanoyl-piperazino-lower alkyl, unsubstituted or lower alkylatedmorpholino-lower alkyl, such as morpholino-lower alkyl ordimethylmorpholino-lower alkyl, or optionally S-oxidisedthio-morpholino-lower alkyl, such as thiomorpholino-lower alkyl orS,S-dioxothiomorpholino-lower alkyl.

Free or esterified or amidated dicarboxy-lower alkyl is, for example,dicarboxy-lower alkyl, di-lower alkoxycarbonyl-lower alkyl,dicarbamoyl-lower alkyl or di-(N-mono- or N,N-di-loweralkylcarbamoyl)-lower alkyl.

Free or esterified or amidated carboxy-(hydroxy)-lower alkyl is, forexample, carboxy-(hydroxy)-lower alkyl, loweralkoxycarbonyl-(hydroxy)-lower alkyl or carbamoyl-(hydroxy)-lower alkyl.

Free or esterified or amidated carboxycycloalkyl-lower alkyl is, forexample, 5- or 6-membered carboxycycloalkyl-lower alkyl, loweralkoxycarbonylcycloalkyl-lower alkyl, carbamoylcycloalkyl-lower alkyl,or N-mono- or N,N-di-lower alkylcarbamoylcyclo-alkyl-lower alkyl.

Unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkylis, for example, sulfamoyl-lower alkyl, lower alkylsulfamoyl-lower alkylor di-lower alkyl-sulfamoyl-lower alkyl.

Unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-loweralkyl is, for example, thiocarbamoyl-lower alkyl, loweralkylthiocarbamoyl-lower alkyl or di-lower alkylthiocarbamoyl-loweralkyl, such as N,N-dimethylthiocarbamoylmethyl.

Heteroaryl that is optionally oxo-substituted, bonded via a carbon atomand optionally hydrogenated, and such a heteroaryl in a lower alkyl thatis substituted by heteroaryl radicals that are optionallyoxo-substituted, bonded via a carbon atom and optionally hydrogenated,contains as optionally hydrogenated heteroaryl radical, for example, anoptionally partially hydrogenated and/or benzo-fused 5-membered aza-,diaza-, triaza-, oxadiaza- or tetraaza-aryl radical or a 6-membered aza-or diaza-aryl radical, and as lower alkyl radical, for example, C₁ -C₇alkyl, preferably C₁ -C₄ alkyl, and is, for example, pyrrolidinyl-loweralkyl, e.g. oxopyrrolidinyl-C₁ -C₄ alkyl, imidazolyl-lower alkyl, e.g.imidazol-4-yl-C₁ -C₄ alkyl, benzimidazolyl-lower alkyl, e.g.benzimidazol-2-yl-C₁ -C₄ alkyl, oxodiazolyl-lower alkyl, e.g.1,2,4-oxadiazol-5-yl-C₁ -C₄ alkyl, pyridyl-lower alkyl, e.g.pyridin-2-yl-C₁ -C₄ alkyl, oxopiperidinyl-C₁ -C₄ alkyl,dioxopiperidinyl-C₁ -C₄ alkyl, oxothiazolyl-C₁ -C₄ alkyl,oxo-oxazolinyl-C₁ -C₄ alkyl or quinolinyl-lower alkyl, e.g.quinolin-2-yl-C₁ -C₄ alkyl, also morpholinocarbonyl-lower alkyl orunsubstituted or N-lower alkanoylated piperidyl-lower alkyl.

Hereinbefore and hereinafter, lower radicals and compounds are to beunderstood as being, for example, those having up to and including 7,preferably up to and including 4, carbon atoms.

5- or 6-Membered carboxycycloalkyl-lower alkyl, loweralkoxycarbonylcycloalkyl-lower alkyl, carbamoylcycloalkyl-lower alkyl,N-mono- or N,N-di-lower alkylcarbamoylcyclo-alkyl-lower alkyl is, forexample, ω-(1-carboxycycloalkyl)-C₁ -C₄ alkyl, ω-(1-loweralkoxycarbonylcycloalkyl)-C₁ -C₄ alkyl, ω-(1-carbamoylcycloalkyl)-C₁ -C₄alkyl, ω-(1-lower alkylcarbamoylcycloalkyl)-C₁ -C₄ alkyl orω-(1-di-lower alkylcarbamoylcycloalkyl)-C₁ -C₄ alkyl, wherein cycloalkylis, for example, cyclopentyl or cyclohexyl, lower alkoxycarbonyl is, forexample, C₁ -C₄ alkoxycarbonyl, such as methoxy- or ethoxycarbonyl,lower alkylcarbamoyl is, for example, C₁ -C₄ alkylcarbamoyl, such asmethylcarbamoyl, di-lower alkylcarbamoyl is, for example, di-C₁ -C₄alkylcarbamoyl, such as dimethylcarbamoyl, and lower alkyl is, forexample, C₁ -C₄ alkyl, such as methyl, ethyl, propyl or butyl,especially (1-carboxycyclopentyl)methyl.

5- or 6-Membered cycloalkoxy-lower alkoxy is, for example,cyclopentyloxy- or cyclohexyloxy-C₁ -C₄ alkoxy, such as cyclopentyloxy-or cyclohexyloxy-methoxy, 2-cyclopentyloxy- or 2-cyclohexyloxy-ethoxy,2- or 3-cyclopentyloxy- or 2- or 3-cyclohexyloxy-propyloxy or4-cyclopentyloxy- or 4-cyclohexyloxy-butyloxy, especiallycyclopentyloxy- or cyclohexyloxy-methoxy.

5- or 6-Membered cycloalkoxy-lower alkyl is, for example,cyclopentyloxy- or cyclohexyloxy-C₁ -C₄ alkyl, such as cyclopentyloxy-or cyclohexyloxy-methyl, 2-cyclopentyloxy- or 2-cyclohexyloxy-ethyl, 2-or 3-cyclopentyloxy- or 2- or 3-cyclohexyloxy-propyl, 2-cyclopentyloxy-or 2-cyclohexyloxy-2-methyl-propyl, 2-cyclopentyloxy- or2-cyclohexyloxy-2-ethyl-butyl or 4-cyclopentyloxy- or4-cyclohexyloxy-butyl, especially cyclopentyloxy- orcyclohexyloxy-methyl.

Amino-lower alkoxy is, for example, amino-C₁ -C₄ alkoxy, such as2-aminoethoxy or 5-aminopentyloxy, also 3-aminopropyloxy or4-aminobutyloxy.

Amino-lower alkyl is, for example, amino-C₁ -C₄ alkyl, such as2-aminoethyl, 3-aminopropyl or 4-aminobutyl.

Carbamoyl-(hydroxy)-lower alkyl is, for example, carbamoyl-C₁ -C₇(hydroxy)alkyl, such as 1-carbamoyl-2-hydroxyethyl.

Carbamoyl-lower alkoxy is, for example, carbamoyl-C₁ -C₄ alkoxy, such ascarbamoylmethoxy, 2-carbamoylethoxy, 3-carbamoylpropyloxy or4-carbamoylbutyloxy, especially carbamoylmethoxy.

Carbamoyl-lower alkyl is, for example, carbamoyl-C₁ -C₇ alkyl, such ascarbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl,2-(3-carbamoyl)propyl, 2-carbamoylpropyl, 3-(1-carbamoyl)propyl,2-(2-carbamoyl)propyl, 2-(carbamoyl-2-methyl)propyl, 4-carbamoylbutyl,1-carbamoylbutyl, 1-(1-carbamoyl-2-methyl)butyl or3-(4-carbamoyl-2-methyl)butyl.

Carboxy-(hydroxy)-lower alkyl is, for example, carboxy-C₁ -C₇(hydroxy)alkyl, such as 1 -carboxy-2-hydroxy-ethyl.

Carboxy-lower alkoxy is, for example, carboxy-C₁ -C₄ alkoxy, such ascarboxymethoxy, 2-carboxyethoxy, 2- or 3-carboxypropyloxy or4-carboxybutyloxy, especially carboxy-methoxy.

Carboxy-lower alkyl is, for example, carboxy-C₁ -C₄ alkyl, such ascarboxymethyl, 2-carboxyethyl, 2- or 3-carboxypropyl,2-carboxy-2-methyl-propyl, 2-carboxy-2-ethyl-butyl or 4-carboxybutyl,especially carboxymethyl.

Cyano-lower alkoxy is, for example, cyano-C₁ -C₄ alkoxy, such ascyanomethoxy, 2-cyano-ethoxy, 2- or 3-cyanopropyloxy or 4-cyanobutyloxy,especially cyanomethoxy.

Cyano-lower alkyl is, for example, cyano-C₁ -C₄ alkyl, such ascyanomethyl, 2-cyanoethyl, 2- or 3-cyanopropyl, 2-cyano-2-methyl-propyl,2-cyano-2-ethyl-butyl or 4-cyanobutyl, especially cyanomethyl.

Di-(N-mono- or N,N-di-lower alkylcarbamoyl)-lower alkyl is, for example,di-(N-mono- or N,N-di-C₁ -C₄ alkylcarbamoyl)-C₁ -C₄ alkyl, such as1,2-di-(N-mono- or N,N-di-C₁ -C₄ alkylcarbamoyl)ethyl or 1,3-di-(N-mono-or N,N-di-C₁ -C₄ alkylcarbamoyl)propyl.

Dicarbamoyl-lower alkyl is, for example, dicarbamoyl-C₁ -C₄ alkyl, suchas 1,2-dicarbamoylethyl or 1,3-dicarbamoylpropyl.

Dicarboxy-lower alkyl is, for example, dicarboxy-C₁ -C₄ alkyl, such as1,2-dicarboxyethyl or 1,3-dicarboxypropyl.

Dimethylmorpholino-lower alkoxy can be N-oxidised and is, for example,2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-C₁ -C₄ alkoxy, such as2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-methoxy,2-(2,6-dimethylmorpholino-or 3,5-dimethylmorpholino)-ethoxy,3-(2,6-dimethylmorpholino-or 3,5-dimethylmorpholino)-propyloxy,2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-3-methyl)propyloxy,or 1- or 2-[4-(2,6-dimethylmorpholino- or3,5-dimethylmorpholino)]-butyloxy.

Dimethylmorpholino-lower alkyl can be N-oxidised and is, for example,2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-C₁ -C₄ alkyl, such as2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-methoxy,2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-ethoxy,3-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-propyl,2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-3-methyl)-propyl,or 1- or 2-[4-(2,6-dimethylmorpholino- or3,5-dimethylmorpholino)]-butyl.

Di-lower alkoxycarbonyl-lower alkyl is, for example, di-loweralkoxycarbonyl-C₁ -C₄ alkyl, such as 1,2-dimethoxycarbonylethyl,1,3-dimethoxycarbonylpropyl, 1,2-dimethoxycarbonylethyl or1,3-diethoxycarbonylpropyl.

Di-lower alkylamino is, for example, di-C₁ -C₄ alkylamino, such asdimethylamino, N-methyl-N-ethylamino, diethylamino,N-methyl-N-propylamino or N-butyl-N-methylamino.

Di-lower alkylamino-lower alkoxy is, for example, N,N-di-C₁ -C₄alkylamino-C₁ -C₄ alkoxy, such as 2-dimethylaminoethoxy,3-dimethylaminopropyloxy, 4-dimethylaminobutyloxy, 2-diethylaminoethoxy,2-(N-methyl-N-ethyl-amino)ethoxy or 2-(N-butyl-N-methyl-amino)ethoxy.

Di-lower alkylamino-lower alkyl is, for example, N,N-di-C₁ -C₄alkylamino-C₁ -C₄ alkyl, such as 2-dimethylaminoethyl,3-dimethylaminopropyl, 4-dimethylaminobutyl, 2-diethylaminoethyl,2-(N-methyl-N-ethyl-amino)ethyl or 2-(N-butyl-N-methyl-amino)ethyl.

Di-lower alkylcarbamoyl-lower alkoxy is, for example, N,N-di-C₁ -C₄alkylcarbamoyl-C₁ -C₄ alkoxy, such as methyl- or dimethyl-carbamoyl-C₁-C₄ alkoxy, such as N-methyl-, N-butyl- orN,N-dimethyl-carbamoylmethoxy, 2-(N-methylcarbamoyl)ethoxy,2-(N-butylcarbamoyl)ethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy,3-(N-methylcarbamoyl)propyloxy, 3-(N-butylcarbamoyl)propyloxy,3-(N,N-dimethylcarbamoyl)propyloxy or 4-(N-methylcarbamoyl)butyloxy,4-(N-butylcarbamoyl)butyloxy or 4-(N,N-dimethylcarbamoyl)butyloxy,especially N-methyl-, N-butyl- or N,N-dimethyl-carbamoylmethoxy.

Di-lower alkylcarbamoyl-lower alkyl is, for example, N,N-di-C₁ -C₄alkylcarbamoyl-C₁ -C₄ alkyl, such as 2-dimethylcarbamoylethyl,3-dimethylcarbamoylpropyl, 2-dimethylcarbamoylpropyl,2-(dimethylcarbamoyl-2-methyl)propyl or2-(1-dimethylcarbamoyl-3-methyl)butyl.

Di-lower alkylsulfamoyl-lower alkyl is, for example, N,N-di-C₁ -C₄alkylsulfamoyl-C₁ -C₄ alkyl, N,N-dimethylsulfamoyl-C₁ -C₄ alkyl, such asN,N-dimethylsulfamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl,3-(N,N-dimethylcarbamoyl)propyl or 4-(N,N-dimethylcarbamoyl)butyl,especially N,N-dimethylcarbamoylmethyl.

Unsubstituted or N-lower alkanoylated piperidyl-lower alkyl is, forexample, 1-C₁ -C₇ -lower alkanoylpiperidin-4-yl-C₁ -C₄ alkyl, such as1-acetylpiperidinylmethyl or 2-(1-acetylpiperidinyl)ethyl.

Optionally partially hydrogenated or N-oxidised pyridyl-lower alkoxy is,for example, optionally partially hydrogenated pyridyl- orN-oxidopyridyl-C₁ -C₄ alkoxy, such as pyridyl- orN-oxidopyridyl-methoxy, 2-pyridylethoxy, 2- or 3-pyridylpropyloxy or4-pyridylbutyloxy, especially 3- or 4-pyridylmethoxy.

Optionally partially hydrogenated or N-oxidised pyridyl-lower alkyl is,for example, optionally partially hydrogenated pyridyl- orN-oxidopyridyl-C₁ -C₄ alkyl, such as pyridyl- or N-oxidopyridyl-methyl,2-pyridylethyl, 2- or 3-pyridylpropyl or 4-pyridylbutyl, especially 3-or 4-pyridylmethyl.

Halo-(hydroxy)-lower alkoxy is, for example, halo-C₂ -C₇(hydroxy)alkoxy, especially halo-C₂ -C₄ (hydroxy)alkoxy, such as3-halo-, such as 3-chloro-2-hydroxy-propyloxy.

Hydroxy-lower alkoxy is, for example, hydroxy-C₂ -C₇ alkoxy, especiallyhydroxy-C₂ -C₄ alkoxy, such as 2-hydroxybutyloxy, 3-hydroxypropyloxy or4-hydroxybutyloxy.

Hydroxy-lower alkyl is, for example, hydroxy-C₂ -C₇ alkyl, especiallyhydroxy-C₂ -C₄ alkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or4-hydroxybutyl.

Hydroxypiperidino-lower alkyl is, for example, 3- or4-hydroxypiperidino-C₁ -C₄ alkoxy, such as 3- or4-hydroxypiperidinomethoxy, 2-(3- or 4-hydroxypiperidino)ethoxy, 3-(3-or 4-hydroxypiperidino)propyloxy or 4-(3- or4-hydroxypiperidino)butyloxy.

Imidazolyl-lower alkyl is, for example, imidazolyl-C₁ -C₄ alkyl, such asimidazol-4-yl-methyl, 2-(imidazol-4-yl)ethyl, 3-(imidazol-4-yl)propyl or4-(imidazol-4-yl)butyl.

Imidazolyl-lower alkoxy is, for example, imidazolyl-C₁ -C₄ alkoxy, suchas imidazol-4-yl-methoxy, 2-(imidazol-4-yl)ethoxy,3-(imidazol-4-yl)propyloxy or 4-(imidazol-4-yl)butyloxy.

Imidazolyl-lower alkyl is, for example, imidazolyl-C₁ -C₄ alkyl, such asimidazol-4-yl-methyl, 2-(imidazol-4-yl)ethyl, 3-(imidazol-4-yl)propyl or4-(imidazol-4-yl)butyl.

Morpholinocarbonyl-lower alkyl is, for example, morpholinocarbonyl-C₁-C₄ alkyl, such as 1-morpholinocarbonylethyl,3-morpholinocarbonylpropyl, or 1-(morpholinocarbonyl-2-methyl)propyl.

Morpholino-lower alkoxy can be N-oxidised and is, for example,morpholino-C₁ -C₄ alkoxy, such as 1-morpholinoethoxy,3-morpholinopropyloxy, or 1-(morpholino-2-methyl)propyloxy.

Morpholino-lower alkyl can be N-oxidised and is, for example,morpholino-C₁ -C₄ alkyl, such as morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl or 1- or 2-(4-morpholino)butyl.

Lower alkanoyl is, for example, C₁ -C₇ alkanoyl, especially C₂ -C₆alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoylamino is, for example, N-C₁ -C₇ alkanoylamino, such asacetylamino or pivaloylamino.

Lower alkanoylamino is, for example, N-C₁ -C₇ alkanoylamino, such asacetylamino or pivaloylamino.

Lower alkanoylamino-lower alkyl is, for example, N-C₁ -C₄alkanoylamino-C₁ -C₄ alkyl, such as 2-acetoxyaminoethyl.

Lower alkanoylamino-lower alkyl is, for example, N-C₁ -C₄alkanoylamino-C₁ -C₄ alkyl, such as 2-acetoxyaminoethyl.

Lower alkanoyl-lower alkoxy (oxo-lower alkoxy) carries the loweralkanoyl group in a position higher than the α-position and is, forexample, C₁ -C₇ alkanoyl-C₁ -C₄ alkoxy, such as 4-acetylbutoxy.

Lower alkanoyloxy-lower alkyl carries the lower alkanoyloxy group in aposition higher than the α-position and is, for example, C₁ -C₇alkanoyloxy-C₁ -C₄ alkyl, such as 4-acetoxy-butyl.

Lower alkanesulfonyl-(hydroxy)-lower alkoxy is, for example, C₁ -C₇alkanesulfonyl-C₁ -C₄ (hydroxy)alkoxy, such as3-methanesulfonyl-2-hydroxy-propyloxy.

Lower alkanesulfonyl-lower alkoxy is, for example, C₁ -C₇alkanesulfonyl-C₁ -C₄ alkoxy, such as methanesulfonylmethoxy or3-methanesulfonyl-2-hydroxy-propyloxy.

Lower alkanesulfonylamino-lower alkoxy is, for example, C₁ -C₇alkanesulfonylamino-C₁ -C₄ alkoxy, such as ethanesulfonylaminomethoxy,2-ethanesulfonylaminoethoxy, 3-ethanesulfonylaminopropyloxy or3-(1,1-dimethylethanesulfonylamino)propyloxy.

Lower alkanesulfonylamino-lower alkyl is, for example, C₁ -C₇alkanesulfonylamino-C₁ -C₄ alkyl, such as ethanesulfonylaminomethyl,2-ethanesulfonylaminoethyl, 3-ethanesulfonylaminopropyl or3-(1,1-dimethylethanesulfonylamino)propyl.

Lower alkanesulfonyl-lower alkyl is, for example, C₁ -C₇alkanesulfonyl-C₁ -C₄ alkyl, such as ethanesulfonylmethyl,2-ethanesulfonylethyl, 3-ethanesulfonylpropyl or3-(1,1-dimethylethanesulfonyl)propyl.

Lower alkenyl is, for example, C₁ -C₇ alkenyl, such as vinyl or allyl.

Lower alkenyloxy is, for example, C₁ -C₇ alkenyloxy, such as allyloxy.

Lower alkenyloxy-lower alkoxy is, for example, C₁ -C₇ alkenyloxy-C₁ -C₄alkoxy, such as allyloxymethoxy.

Lower alkenyloxy-lower alkyl is, for example, C₁ -C₇ alkenyloxy-C₁ -C₄alkyl, such as allyloxymethyl.

Lower alkoxy is, for example, C₁ -C₇ alkoxy, preferably C₁ -C₅ alkoxy,such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,secondary butyloxy, tertiary butyloxy, pentyloxy or a hexyloxy orheptyloxy group.

Lower alkoxycarbonyl is, for example, C₁ -C₇ alkoxycarbonyl, preferablyC₁ -C₅ alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl,isobutyloxycarbonyl, secondary butyloxycarbonyl, tertiary butyloxy,pentyloxycarbonyl or a hexyloxycarbonyl or heptyloxycarbonyl group.

Lower alkoxycarbonyl-(hydroxy)-lower alkyl is, for example, C₁ -C₄alkoxycarbonyl-C₁ -C₇ (hydroxy)alkyl, such as 1-methoxycarbonyl- or1-ethoxycarbonyl-2-hydroxy-ethyl.

Lower alkoxycarbonylamino-lower alkoxy is, for example, C₁ -C₇alkoxycarbonylamino-C₂ -C₇ alkoxy, preferably C₂ -C₅alkoxycarbonylamino-C₂ -C₇ alkoxy, such as methoxycarbonylamino-C₂ -C₇alkoxy, ethoxycarbonylamino-C₂ -C₇ alkoxy, propyloxycarbonylamino-C₂ -C₇alkoxy, isobutyloxycarbonylamino-C₂ -C₇ alkoxy, butyloxycarbonylamino-C₂-C₇ alkoxy, isobutyloxycarbonylamino-C₂ -C₇ alkoxy, secondarybutyloxycarbonylamino-C₂ -C₇ alkoxy or tertiary butyloxyamino-C₂ -C₇alkoxy, wherein C₂ -C₇ alkoxy is, for example, methoxy, ethoxy,propyloxy, butyloxy, pentyloxy or hexyloxy.

Lower alkoxycarbonylamino-lower alkyl is, for example, C₁ -C₇alkoxycarbonylamino-C₂ -C₇ alkyl, preferably C₂ -C₅alkoxycarbonylamino-C₂ -C₇ alkyl, such as methoxycarbonyl-C₂ -C₇ alkyl,ethoxycarbonylamino-C₂ -C₇ -alkyl, propyloxycarbonylamino-C₂ -C₇ -alkylisopropyloxycarbonylamino-C₂ -C₇ alkyl, butyloxycarbonylamino-C₂ -C₇alkyl, isobutyloxycarbonylamino-C₂ -C₇ alkyl, secondarybutyloxycarbonylamino-C₂ -C₇ alkyl or tertiary butyloxyamino-C₂ -C₇alkyl, wherein C₂ -C₇ alkyl is, for example, methyl, ethyl, propyl,butyl, pentyl or hexyl.

Lower alkoxycarbonyl-lower alkoxy is, for example, C₁ -C₄alkoxycarbonyl-C₁ -C₄ alkoxy, such as methoxycarbonyl- orethoxycarbonyl-methoxy, 2-methoxycarbonyl- or 2-ethoxycarbonyl-ethoxy,2- or 3-methoxycarbonyl- or 2- or 3-ethoxycarbonyl-propyloxy or4-methoxycarbonyl- or 4-ethoxycarbonyl-butyloxy, especiallymethoxycarbonyl- or ethoxycarbonyl-methoxy or 3-methoxycarbonyl- or3-ethoxycarbonyl-propyloxy.

Lower alkoxycarbonyl-lower alkyl is, for example, C₁ -C₄alkoxycarbonyl-C₁ -C₄ alkyl, such as methoxycarbonyl- orethoxycarbonyl-methoxy, 2-methoxycarbonyl- or 2-ethoxycarbonyl-ethoxy,3-methoxycarbonyl- or 3-ethoxycarbonyl-propyloxy or4-ethoxycarbonylbutyloxy.

Lower alkoxy-lower alkenyl is, for example, C₁ -C₄ alkoxy-C₂ -C₄alkenyl, such as 4-methoxybut-2-enyl.

Lower alkoxy-lower alkoxy is, for example, C₁ -C₄ alkoxy-C₂ -C₄ alkoxy,such as 2-methoxy-, 2-ethoxy- or 2-propyloxy-ethoxy, 3-methoxy- or3-ethoxy-propyloxy or 4-methoxybutyloxy, especially 3-methoxypropyloxyor 4-methoxybutyloxy.

Lower alkoxy-lower alkoxy-lower alkyl is, for example, C₁ -C₄ alkoxy-C₁-C₄ alkoxy-C₁ -C₄ alkyl, such as 2-methoxy-, 2-ethoxy- or2-propyloxy-ethoxymethyl, 2-(2-methoxy-, 2-ethoxy- or2-propyloxy-ethoxy)ethyl, 3-(3-methoxy- or 3-ethoxy-propyloxy)propyl or4-(2-methoxybutyloxy)butyl, especially 2-(3-methoxypropyloxy)ethyl or2-(4-methoxybutyloxy)ethyl.

Lower alkoxy-lower alkyl is, for example, C₁ -C₄ alkoxy-C₁ -C₄ alkyl,such as ethoxymethyl, propyloxymethyl, butyloxymethyl, 2-methoxy-,2-ethoxy- or 2-propyloxy-ethyl, 3-methoxy- or 3-ethoxy-propyl or4-methoxybutyl, especially 3-methoxypropyl or 4-methoxybutyl.

Lower alkoxypiperidino-lower alkyl is, for example, piperidino-,hydroxypiperidino- or lower alkoxypiperidino-C₁ -C₄ alkyl, such aspiperidinomethyl, 4-hydroxypiperidinomethyl or 4-C₁ -C₄ alkoxy-, such as4-methoxy-piperidinomethyl.

Lower alkoxypiperidino-lower alkyl is, for example, C₁ -C₄alkoxypiperidino-C₁ -C₄ alkyl, such as 4-C₁ -C₄ alkoxy-piperidinomethyl,especially 4-methoxypiperidinomethyl.

Lower alkyl may be straight-chained or branched and/or bridged and is,for example, corresponding C₁ -C₇ alkyl, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, or apentyl, hexyl or heptyl group. Lower alkyl R₂ or R₃ is especially C₂ -C₇alkyl, lower alkyl R₅ or R₇ is especially branched C₃ -C₇ alkyl andlower alkyl R₈ or R₃ is, for example, straight-chained, branched orbridged C₃ -C₇ alkyl.

Lower alkylamino is, for example, C₁ -C₄ alkylamino, such asmethylamino, ethylamino, propylamino, butylamino, isobutylamino,secondary butylamino or tertiary butylamino.

Lower alkylamino-lower alkoxy is, for example, C₁ -C₄ alkylamino-C₁ -C₄alkoxy, such as propylaminomethoxy, 2-methylamino-, 2-ethylamino-,2-propylamino- or 2-butylamino-ethoxy, 3-ethylamino- or3-propylamino-propyloxy or 4-methylaminobutoxy.

Lower alkylamino-lower alkyl is, for example, C₁ -C₄ alkylamino-C₁ -C₄alkyl, such as propylaminomethyl, 2-methylamino-, 2-ethylamino-,2-propylamino- or 2-butylamino-ethyl, 3-ethylamino- or3-propylamino-propyl or 4-methylaminobutyl.

Lower alkylcarbamoyl-lower alkoxy is, for example, N-C₁ -C₇alkylcarbamoyl-C₁ -C₄ alkoxy, such as methyl- or dimethyl-carbamoyl-C₁-C₄ alkoxy, e.g. methylcarbamoylmethoxy, 2-methylcarbamoylethoxy or3-methylcarbamoylpropyloxy.

Lower alkylenedioxy is, for example, methylenedioxy or ethylenedioxy,but can also be 1,3- or 1,2-propylenedioxy.

Lower alkylsulfamoyl-lower alkyl is, for example, N-C₁ -C₇alkylsulfamoyl-C₁ -C₄ alkyl, such as N-methyl-, N-ethyl-, N-propyl- orN-butyl-sulfamoyl-C₁ -C₄ alkyl, such as N-methyl-, N-ethyl-, N-propyl-or N-butyl-sulfamoylmethyl, 2-(N-methylsulfamoyl)ethyl,2-(N-butylsulfamoyl)ethyl, 3-(N-methylsulfamoyl)propyl,3-(N-butylsulfamoyl)propyl, or 4-(N-methylsulfamoyl)butyl,4-(N-butylsulfamoyl)butyl or 4-(N,N-dimethylsulfamoyl)butyl, especiallyN-methyl-, N-butyl- or N,N-dimethyl-sulfamoylmethyl.

Lower alkylthio-(hydroxy)-lower alkoxy is, for example, N-C₁ -C₄alkylthio-C₁ -C₄ (hydroxy)alkoxy, such as2-hydroxy-3-methylthiopropyloxy.

Oxazolyl-lower alkyl is, for example, oxazolyl-C₁ -C₄ alkyl, such as2-(1,2,4-oxadiazol-5-yl)ethyl, 3-(1,2,4-oxadiazol-5-yl)propyl or4-(1,2,4-oxadiazol-5-yl)butyl.

Lower alkylthio-lower alkoxy is, for example, N-C₁ -C₄ alkylthio-C₁ -C₄alkoxy, such as methylthio-C₁ -C₄ alkoxy, e.g. methylthiomethoxy,2-methylthioethoxy or 3-methylthiopropyloxy.

Lower alkylthio-lower alkyl is, for example, N-C₁ -C₄ alkylthio-C₁ -C₄alkyl, such as methylthio-C₁ -C₄ alkyl, e.g. methylthiomethyl,2-methylthioethyl or 3-methylthiopropyl.

N'-Lower alkanoylpiperazino-lower alkoxy is, for example, N'-loweralkanoylpiperazino-C₁ -C₄ alkoxy, such as 4-acetylpiperazinomethoxy.

N'-Lower alkanoylpiperazino-lower alkyl is, for example, N'-C₂ -C₇-lower alkanoylpiperazino-C₁ -C₄ alkyl, such as4-acetylpiperazinomethyl.

N'-Lower alkylpiperazino-lower alkyl is, for example, N'-C₁ -C₄alkylpiperazino-C₁ -C₄ alkyl, such as 4-methylpiperazinomethyl.

Oxo-lower alkoxy is, for example, oxo-C₁ -C₄ alkoxy, such as3,3-dimethyl-2-oxo-butyloxy.

Piperazino-lower alkyl is, for example, piperazino-C₁ -C₄ alkyl, such aspiperazinomethyl, 2-piperazinoethyl or 3-piperazinopropyl.

Piperidino-lower alkoxy is, for example, piperidino-C₁ -C₄ alkoxy, suchas piperidinomethoxy, 2-piperidinoethoxy or 3-piperidinopropyloxy.

Piperidino-lower alkyl is, for example, piperidino-C₁ -C₄ alkyl, such aspiperidinomethyl, 2-piperidinoethyl or 3-piperidinopropyl.

Polyhalo-lower alkanesulfonylamino-lower alkoxy is, for example,trifluoro-C₁ -C₇ alkanesulfonyl-C₁ -C₄ alkoxy, such astrifluoromethanesulfonylaminobutyloxy.

Polyhalo-lower alkanesulfonylamino-lower alkyl is, for example,trifluoro-C₁ -C₇ alkanesulfonyl-C₁ -C₄ alkyl, such astrifluoromethanesulfonylaminobutyl.

Pyrimidinyl-lower alkoxy is, for example, pyrimidinyl-C₁ -C₄ alkoxy,such as pyrimidinylmethoxy, 2-pyrimidinylethoxy or3-pyrimidinylpropyloxy.

Pyrimidinyl-lower alkyl is, for example, pyrimidinyl-C₁ -C₄ alkyl, suchas pyrimidinylmethyl, 2-pyrimidinylethyl or 3-pyrimidinylpropyl.

Pyrrolidino-lower alkoxy is, for example, pyrrolidino-C₂ -C₄ alkoxy,such as 2-pyrrolidinoethoxy or 3-pyrrolidinopropyloxy.

Pyrrolidino-lower alkyl is, for example, pyrrolidino-C₁ -C₄ alkyl, suchas pyrrolidinomethyl, 2-pyrrolidinoethyl or 3-pyrrolidinopropyl.

S,S-Dioxothiomorpholino-lower alkyl is, for example,S,S-dioxothiomorpholino-C₁ -C₄ alkyl, such asS,S-dioxothiomorpholinomethyl or 2-(S,S-dioxo)thiomorpholinoethyl.

S-Oxothiomorpholino-lower alkyl is, for example, S-oxothiomorpholino-C₁-C₄ alkyl, such as S-oxothiomorpholinomethyl or2-(S-oxo)thiomorpholinoethyl.

Sulfamoyl-lower alkyl is, for example, sulfamoyl-C₁ -C₄ alkyl, such assulfamoyl-C₁ -C₄ alkyl, such as sulfamoylmethyl, 2-sulfamoylethyl,3-sulfamoylpropyl or 4-sulfamoylbutyl.

Tetrazolyl-lower alkyl is, for example, tetrazolyl-C₁ -C₄ alkyl, such astetrazol-5-ylmethyl, 2-(tetrazol-5-yl)ethyl, 3-(tetrazol-5-yl)propyl or4-(tetrazol-4-yl)butyl.

Thiazolinyl-lower alkoxy is, for example, thiazolinyl-C₁ -C₄ alkoxy,such as thiazolinylmethoxy, 2-thiazolinylmethoxy or3-thiazolinylpropyloxy.

Thiazolinyl-lower alkyl is, for example, thiazolinyl-C₁ -C₄ alkyl, suchas thiazolinylmethyl, 2-thiazolinylethyl or 3-thiazolinylpropyl.

Thiazolyl-lower alkoxy is, for example, thiazolyl-C₁ -C₄ alkoxy, such asthiazolylmethoxy, 2-thiazolylethoxy or 3-thiazolylpropyloxy.

Thiazolyl-lower alkyl is, for example, thiazolyl-C₁ -C₄ alkyl, such asthiazolylmethyl, 2-thiazolylethyl or 3-thiazolylpropyl.

Thiomorpholino-lower alkyl or S,S-dioxothiomorpholino-lower alkyl is,for example, thiomorpholino-C₁ -C₄ alkyl, such as -methyl or -ethyl, orS,S-dioxothiomorpholino-C₁ -C₄ alkyl, such as -methyl or -ethyl.

Depending on whether asymmetric carbon atoms are present, the compoundsof the invention can be present as mixtures of isomers, especially asracemates, or in the form of pure isomers, especially optical antipodes.

Salts of compounds having salt-forming groups are especially acidaddition salts, salts with bases or, where several salt-forming groupsare present, can also be mixed salts or internal salts.

Salts are especially the pharmaceutically acceptable or non-toxic saltsof compounds of formula I.

Such salts are formed, for example, by compounds of formula I having anacid group, for example a carboxy group or a sulfo group, and are, forexample, salts thereof with suitable bases, such as non-toxic metalsalts derived from metals of groups Ia, Ib, IIa and IIb of the PeriodicTable of the Elements, for example alkali metal salts, especiallylithium, sodium or potassium salts, or alkaline earth metal salts, forexample magnesium or calcium salts, also zinc salts or ammonium salts,as well as salts formed with organic amines, such as unsubstituted orhydroxy-substituted mono-, di- or tri-alkylamines, especially mono-, di-or tri-lower alkylamines, or with quaternary ammonium bases, for examplewith methyl-, ethyl-, diethyl- or triethyl-amine, mono-, his- ortris-(2-hydroxy-lower alkyl)-amines, such as ethanol-, diethanol- ortriethanol-amine, tris-(hydroxymethyl)-methylamine or2-hydroxy-tert-butylamines, N,N-di-lower alkyl-N-(hydroxy-loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine, orN-methyl-D-glucamine, or quaternary ammonium hydroxides, such astetrabutylammonium hydroxide. The compounds of formula I having a basicgroup, for example an amino group, can form acid addition salts, forexample with suitable inorganic acids, for example hydrohalic acids,such as hydrochloric acid or hydrobromic acid, or sulfuric acid withreplacement of one or both protons, phosphoric acid with replacement ofone or more protons, e.g. orthophosphoric acid or metaphosphoric acid,or pyrophosphoric acid with replacement of one or more protons, or withorganic carboxylic, sulfonic, sulfo or phosphonic acids or N-substitutedsulfamic acids, for example acetic acid, propionic acid, glycolic acid,succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid,fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid,glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid,2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinicacid, as well as with amino acids, such as the α-amino acids mentionedhereinbefore, and with methanesulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,benzenesulfonic acid, 4-toluenesulfonic acid, naphthalene-2-sulfonicacid, 2- or 3-phosphoglycerate, glucose-6-phosphate, orN-cyclohexylsulfamic acid (forming cyclamates) or with other acidicorganic compounds, such as ascorbic acid. Compounds of formula I havingacid and basic groups can also form internal salts.

For isolation and purification purposes it is also possible to usepharmaceutically unacceptable salts.

The compounds of the present invention have enzyme-inhibitingproperties. In particular, they inhibit the action of the natural enzymerenin. The latter passes from the kidneys into the blood where iteffects the cleavage of angiotensinogen, releasing the decapeptideangiotensin I which is then cleaved in the lungs, the kidneys and otherorgans to form the octapeptide angiotensinogen II. The octapeptideincreases blood pressure both directly by arterial vasoconstriction andindirectly by liberating from the adrenal glands thesodium-ion-retaining hormone aldosterone, accompanied by an increase inextracellular fluid volume. That increase can be attributed to theaction of angiotensin II. Inhibitors of the enzymatic activity of reninbring about a reduction in the formation of angiotensin I. As a result asmaller amount of angiotensin II is produced. The reduced concentrationof that active peptide hormone is the direct cause of the hypotensiveeffect of renin inhibitors.

The action of renin inhibitors is demonstrated inter alia experimentallyby means of in vitro tests, the reduction in the formation ofangiotensin I being measured in various systems (human plasma, purifiedhuman renin together with synthetic or natural renin substrate). Interalia the following in vitro test is used: an extract of human renin fromthe kidney (0.5 mGU [milli-Goldblatt units]/ml) is incubated for onehour at 37° C. and pH 7.2 in 1-molar aqueous2-N-(tris-hydroxymethylmethyl)amino-ethanesulfonic acid buffer solutionwith 23 μg/ml of synthetic renin substrate, the tetradecapeptideH-Asp-Arg-Val-Tyr-Ile-His-ProPhe-His-Leu-Leu-Val-Tyr-Ser-OH. The amountof angiotensin I formed is determined by radioimmunoassay. Each of theinhibitors according to the invention is added to the incubation mixtureat different concentrations. The IC₅₀ is defined as the concentration ofa particular inhibitor that reduces the formation of angiotensin I by50%. In the in vitro systems the compounds of the present inventionexhibit inhibiting activities at minimum concentrations of fromapproximately 10⁻⁶ to approximately 10⁻¹⁰ mol/l.

In animals deficient in salt, renin inhibitors bring about a reductionin blood pressure. Human renin differs from the renin of other species.In order to test inhibitors of human renin, primates (marmosets,Callithrix jacchus) are used, because human renin and primate renin aresubstantially homologous in the enzymatically active region. Inter aliathe following in vivo test is used: the test compounds are tested onnormotensive marmosets of both sexes having a body weight ofapproximately 350 g that are conscious, allowed to move freely and intheir normal cages. The blood pressure and heart rate are measured via acatheter in the descending aorta and recorded radiometrically. Theendogenous release of renin is stimulated by the combination of a 1-weeklow-salt diet and a single intramuscular injection of furosemide(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (5mg/kg). 16 hours after the injection of furosemide the test compoundsare administered either directly into the femoral artery using aninjection cannula or, in the form of a suspension or solution, via anoesophageal tube into the stomach, and their action on the bloodpressure and heart rate are evaluated. In the in vivo test described,the compounds of the present invention have hypotensive action at dosesof from approximately 0.003 to approximately 0.3 mg/kg i.v. and at dosesof from approximately 0.31 to approximately 30 mg/kg p.o.

The compounds of the present invention also have the property ofregulating, especially reducing, intra-ocular pressure.

The extent of the reduction in intra-ocular pressure afteradministration of a pharmaceutical active ingredient of formula (I)according to the present invention can be determined, for example, inanimals, for example rabbits or monkeys. Two typical experimentalprocedures that illustrate the present invention, but are not intendedto limit it in any way, are described hereinafter.

The in vivo test on a rabbit of the "Fauve de Bourgogne" type todetermine the intraocular-pressure-reducing activity of topicallyapplied compositions can be designed, for example, as follows. Theintra-ocular pressure (IOP) is measured using an aplanation tonometerboth before the experiment and at regular intervals of time. After alocal anaesthetic has been administered, the suitably formulated testcompound is applied topically in a precisely defined concentration (e.g.0.000001-5% by weight) to one eye of the animal in question. Thecontralateral eye is treated, for example, with physiological saline.The measured values thus obtained are evaluated statistically.

The in vivo tests on monkeys of the species Macaca Fascicularis todetermine the intraocular-pressure-reducing activity of topicallyapplied compositions can be carried out, for example, as follows. Thesuitably formulated test compound is applied in a precisely definedconcentration (e.g. 0.000001-5% by weight) to one eye of each monkey.The other eye of the monkey is treated correspondingly, for example withphysiological saline. Before the start of the test the animals areanaesthetised with intramuscular injections of, for example, ketamine.At regular intervals of time, the intra-ocular pressure (IOP) ismeasured. The test is carried out and evaluated in accordance with therules of "good laboratory practice" (GLP).

The compounds of the present invention can be used in the treatment ofhypertension, congestive heart failure, cardiac hypertrophy, cardiacfibrosis, cardiomyopathy post-infarction, complications resulting fromdiabetes, such as nephropathy, vasculopathy and neuropathy, diseases ofthe coronary vessels, restenosis following angioplasty, raisedintra-ocular pressure, glaucoma, abnormal vascular growth,hyperaldosteronism, anxiety states and cognitive disorders.

The groups of compounds mentioned below are not to be regarded asexclusive; rather, for example in order to replace general definitionswith more specific definitions, parts of those groups of compounds canbe interchanged or exchanged for the definitions given above, oromitted, as appropriate.

The invention relates especially to compounds of formula I wherein

R₁ is hydrogen, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-loweralkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy,carbamoyl-lower alkoxy or N-mono- or N,N-di-lower alkylcarbamoyl-loweralkoxy,

R₂ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy-lower alkyl, loweralkoxy-lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy, loweralkanoyloxy-lower alkyl, hydroxy-lower alkoxy, halo-(hydroxy)-loweralkoxy, lower alkanesulfonyl-(hydroxy)-lower alkoxy, amino-lower alkyl,lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, loweralkanoylamino-lower alkyl, lower alkoxycarbonyl-amino-lower alkyl,amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkoxycarbonyl-amino-lower alkoxy, oxo-lower alkoxy, lower alkoxy,cycloalkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, loweralkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-loweralkoxy, lower alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl,lower alkanoyl-lower alkoxy, lower alkylthio-lower alkoxy, loweralkanesulfonyl-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy,aryl-lower alkoxy, thiazolylthio-lower alkoxy or thiazolinylthio-loweralkoxy, imidazolylthio-lower alkoxy, optionally N-oxidisedpyridylthio-lower alkoxy, pyrimidinylthio-lower alkoxy, cyano-loweralkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy,N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy, carboxy-loweralkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl orN-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl,

R₃ is lower alkyl, polyhalo-lower alkyl, lower alkoxy-lower alkyl,cycloalkoxy-lower alkyl, hydroxy-lower alkyl, lower alkylthio-loweralkyl, lower alkanesulfonyl-lower alkyl, optionally partiallyhydrogenated or N-oxidised pyridyl-lower alkyl, thiazolyl-thio-loweralkyl or thiazolinylthio-lower alkyl, imidazolylthio-lower alkyl,optionally N-oxidised pyridylthio-lower alkyl, pyrimidinylthio-loweralkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-loweralkylamino-lower alkyl, lower alkanoyl-amino-lower alkyl, loweralkanesulfonylamino-lower alkyl, polyhalo-loweralkane-sulfonylamino-lower alkyl, pyrrolidino-lower alkyl,piperidino-lower alkyl, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkyl, morpholino-lower alkyl,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothio-morpholino-loweralkyl, cyano-lower alkyl, carboxy-lower alkyl, loweralkoxy-carbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- orN,N-di-lower alkyl-carbamoyl-lower alkyl, cycloalkyl; phenyl or naphthylthat is unsubstituted or mono-, di- or tri-substituted by lower alkyl,lower alkoxy, hydroxy, lower alkylamino, di-lower alkylamino, halogenand/or by trifluoromethyl; hydroxy, lower alkoxy, cycloalkoxy, loweralkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy;phenyl-lower alkoxy or naphthyl-lower alkoxy that is unsubstituted ormono-, di- or tri-substituted by lower alkyl, lower alkoxy, hydroxy,lower alkylamino, di- lower alkylamino, halogen and/or bytrifluoromethyl; lower alkoxy, polyhalo-lower alkoxy, loweralkylthio-lower alkoxy, lower alkanesulfonyl-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally partially or fullyhydrogenated heteroarylthio-lower alkoxy, such as thiazolylthio-loweralkoxy or thiazolinylthio-lower alkoxy, imidazolylthio-lower alkoxy,optionally N-oxidised pyridylthio-lower alkoxy, pyrimidinylthio-loweralkoxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkanesulfonylamino-lower alkoxy, polyhalo-loweralkanesulfonylamino-lower alkoxy, pyrrolidino-lower alkoxy,piperidino-lower alkoxy, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkoxy, morpholino-lower alkoxy,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothiomorpholino-loweralkoxy, cyano-lower alkoxy, carboxy-lower alkoxy, loweralkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy or N-mono- orN,N-di-lower alkylcarbamoyl-lower alkoxy or together with R₄ is loweralkylenedioxy or a fused-on benzo or cyclohexeno ring,

R₄ together with R₃ is lower alkylenedioxy or a fused-on benzo orcyclohexeno ring, or is hydrogen, lower alkyl, hydroxy, lower alkoxy orcycloalkoxy,

X is methylene or hydroxymethylene,

R₅ is lower alkyl or cycloalkyl,

R₆ is amino, lower alkylamino, di-lower alkylamino or loweralkanoylamino,

R₇ is lower alkyl, lower alkenyl, cycloalkyl, or phenyl- ornaphthyl-lower alkyl that is unsubstituted or mono-, di- ortri-substituted by lower alkyl, lower alkoxy, hydroxy, lower alkylamino,di-lower alkylamino, halogen and/or by trifluoromethyl, and

R₈ is lower alkyl, cycloalkyl, hydroxy-lower alkyl, loweralkanoyloxy-lower alkyl, lower alkoxy-lower alkyl or loweralkenyloxy-lower alkyl, amino-lower alkyl, lower alkanoylamino-loweralkyl, N-mono- or N,N-di-lower alkylamino-lower alkyl, optionallyhydroxylated or lower alkoxylated piperidino-lower alkyl, such aspiperidino-lower alkyl, hydroxypiperidino-lower alkyl or loweralkoxypiperidino-lower alkyl, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkyl, unsubstituted or loweralkylated morpholino-lower alkyl, such as morpholino-lower alkyl ordimethylmorpholino-lower alkyl, or optionally S-oxidisedthiomorpholino-lower alkyl, such as thiomorpholino-lower alkyl,S,S-dioxothiomorpholino-lower alkyl, carboxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- orN,N-di-lower alkylcarbamoyl-lower alkyl, dicarboxy-lower alkyl, di-loweralkoxycarbonyl-lower alkyl, dicarbamoyl-lower alkyl, di-(N-mono- orN,N-di-lower alkylcarbamoyl)-lower alkyl, carboxy-(hydroxy)-lower alkyl,lower alkoxy-carbonyl-(hydroxy)-lower alkyl or carbamoyl-(hydroxy)-loweralkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl,sulfamoyl-lower alkyl, lower alkyl-sulfamoyl-lower alkyl, di-loweralkylsulfamoyl-lower alkyl, thiocarbamoyl-lower alkyl, loweralkylthiocarbamoyl-lower alkyl, di-lower alkylthiocarbamoyl-lower alkyl,pyrrolidinyl, imidazolyl, benzimidazolyl, oxadiazolyl, pyridyl,oxopiperidinyl, quinolinyl, unsubstituted or N-lower alkanoylatedpiperidyl or pyrrolidinyl, imidazolyl-lower alkyl, benzimidazolyl-loweralkyl, oxadiazolyl-lower alkyl, pyridyl-lower alkyl, unsubstituted orN-lower alkanoylated piperidyl-lower alkyl or pyrrolidinyl-lower alkyl,oxopiperidinyl-lower alkyl, quinolinyl-lower alkyl,morpholino-carbonyl-lower alkyl or unsubstituted or N-lower alkanoylatedpiperidyl-lower alkyl,

and the salts thereof.

The invention relates especially to compounds of formula I wherein

R₁ is hydrogen,

R₂ is lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy,lower alkoxy-lower alkoxy-lower alkyl; phenyl-lower alkoxy that isunsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,halogen, nitro and/or by amino; optionally N-oxidised pyridyl-loweralkoxy, lower alkylthio-lower alkoxy, lower alkane-sulfonyl-loweralkoxy, lower alkanoyl-lower alkoxy, optionally N-oxidised pyridyl-loweralkoxy, cyano-lower alkoxy, carboxy-lower alkoxy, loweralkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy, loweralkylcarbamoyl-lower alkoxy or di-lower alkylcarbamoyl-lower alkoxy,

R₃ is hydrogen, lower alkyl, hydroxy, lower alkoxy or polyhalo-loweralkoxy or together with R₄ is lower alkylenedioxy,

R₄ is hydrogen or together with R₃ is lower alkylidenedioxy,

X is methylene or hydroxymethylene,

R₅ is lower alkyl or cycloalkyl,

R₆ is amino, lower alkylamino, di-lower alkylamino or loweralkanoylamino,

R₇ is lower alkyl, and

R₈ is lower alkyl, hydroxy,lower alkyl, lower alkanoyl-lower alkyl,lower alkoxy-lower alkyl, lower alkenyloxy-lower alkyl, amino-loweralkyl, lower alkanoylamino-lower alkyl, such as 2-(C₁ -C₄alkanoylamino)-2-methyl-propyl, such as 2-acetylamino-2-methyl-propyl or2-formylamino-2-methyl-propyl, N-mono- or N,N-di-lower alkylamino-loweralkyl, piperidino-lower alkyl, hydroxypiperidino-lower alkyl, loweralkoxypiperidino-lower alkyl, morpholino-lower alkyl,dimethylmorpholino-lower alkyl, thiomorpholino-lower alkyl,S,S-dioxothiomorpholino-lower alkyl, carboxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- orN,N-di-lower alkylcarbamoyl-lower alkyl, carboxy-(hydroxy)-lower alkyl,lower alkoxycarbonyl-(hydroxy)-lower alkyl, carbamoyl-(hydroxy)-loweralkyl, 5- or 6-membered carboxycycloalkyl-lower alkyl, 5- or 6-memberedlower alkoxycarbonyl-cycloalkyl-lower alkyl, 5- or 6-memberedcarbamoylcycloalkyl-lower alkyl, 5- or 6-membered N-mono- orN,N-di-lower alkylcarbamoylcycloalkyl-lower alkyl, cyano-lower alkyl,lower alkanesulfonyl-lower alkyl, sulfamoyl-lower alkyl, loweralkylsulfamoyl-lower alkyl, or di-lower alkylsulfamoyl-lower alkyl,imidazolyl-lower alkyl, oxopyrrolidinyl-lower alkyl,benzimidazolyl-lower alkyl, oxadiazolyl-lower alkyl, pyridyl-loweralkyl, oxopiperidinyl-lower alkyl or quinolinyl-lower alkyl,piperidin-4-yl-lower alkyl or 1-C₁ -C₇ -loweralkanoylpiperidin-4-yl-lower alkyl,

and the salts thereof.

The invention relates above all to compounds of formula I wherein

R₁ and R₄ are hydrogen,

R₂ is C₁ -C₄ alkoxy-C₁ -C₄ alkoxy, such as 3-methoxypropyloxy, or C₁ -C₄alkoxy-C₁ -C₄ alkyl, such as 4-methoxybutyl,

R₃ is C₁ -C₄ alkyl, such as isopropyl or tert-butyl, or C₁ -C₄ alkoxy,such as methoxy,

R₆ is amino,

X is methylene,

R₅ and R₇ are branched C₁ -C₄ alkyl, such as isopropyl, and

R₈ is carbamoyl-C₁ -C₄ alkyl, such as 2- or 3-carbamoylpropyl,2-(3-carbamoyl)propyl or 1-(2-carbamoyl-2-methyl)propyl, N-C₁ -C₄alkylcarbamoyl-C₁ -C₄ alkyl, such as 3-(N-methylcarbamoyl)propyl,1-(N-methylcarbamoyl)prop-2-yl, 2-(N-methyl-carbamoyl)prop-1-yl,especially 2(R)-(N-methylcarbamoyl)prop-1-yl, N,N-di-C₁ -C₄alkylcarbamoyl-C₁ -C₄ alkyl, such as N,N-dimethylcarbamoylmethyl or2-(N,N-dimethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl,morpholino-C₁ -C₄ alkyl, such as 2-morpholinoethyl, 3-morpholinopropylor 1-(2-morpholino-2-methyl)propyl, thiomorpholino-C₁ -C₄ alkyl, such as2-thiomorpholinoethyl, 4-(1-C₁ -C₄ alkanoylpiperidyl)-C₁ -C₄ alkyl, suchas 2-[4-(1-acetyl)piperidinyl]ethyl, 2-oxopyrrolidinyl-C₁ -C₄ alkyl,such as 2-oxopyrrolidin-5(S)-ylmethyl or 2-oxopyrrolidin-5(R)-ylmethyl,

and the salts thereof.

Especially effective are those compounds of formula I wherein at leastone, for example one, two, or preferably all four, of the asymmetriccarbon atoms of the main chain have the stereochemical configurationshown in formula Ia ##STR3## the variables each being as defined above,and the pharmaceutically acceptable salts thereof.

Accordingly, the invention relates preferably to compounds of formula Iwherein at least one, for example one, two, or preferably all four, ofthe asymmetric carbon atoms of the main chain have the stereochemicalconfiguration shown in formula Ia.

The invention relates very especially to those of the above-definedcompounds of formulae I and Ia that are described as being preferredwherein X is methylene.

The invention relates specifically to the compounds of formula Imentioned in the Examples and to the salts thereof, especially thepharmaceutically acceptable salts thereof.

The process according to the invention for the preparation of compoundsof formula I comprises

a) reacting a compound of formula II ##STR4## wherein X₁ is lower alkyl,lower alkanoyl or an amino-protecting group,

X₂ is hydrogen or together with X₃ is a bivalent protecting group,

X₃ is hydrogen or a hydroxy-protecting group or together with X₂ is abivalent protecting group or together with X₄ is a direct bond,

X₄ is free or reactively etherified or esterified hydroxy or togetherwith X₃ is a direct bond, and

R₁, R₂, R₃, R₄, X, R₅, R₆ and R₇ are as defined for formula I, with anamine of formula III

    H.sub.2 N--R.sub.8                                         (III),

wherein

R₈ has one of the meanings given for formula I, with the formation of anamide bond, and removing any protecting groups present, or

b) in a carboxylic acid amide of formula IV ##STR5## wherein R₁, R₂, R₃,R₄, X, R₅, R₆, R₇ and R₈ are as defined for formula I and R'₇ is a loweralkylidene or aryl-lower alkylidene group corresponding to the loweralkyl or aryl-lower alkyl group R₇, free functional groups beingpresent, if desired, in protected form, or in a salt thereof, reducingthe group R'₇ to R₇ by treatment with a hydrogenating agent, or

c) for the preparation of compounds of formula I wherein R₆ is amino, ina 5-azidocarboxylic acid derivative of formula V ##STR6## wherein R₁,R₂, R₃, R₄, R₅, R₇ and R₈ are as defined for formula I, X' is methyleneor free or esterified or etherified hydroxymethyl, and free functionalgroups are present, if desired, in protected form, or in a salt thereof,reducing the azido group to amino, if desired with the freeing ofhydroxymethyl X or the reduction of X' to methylene X, and removing anyprotecting groups present, and, if desired, converting a compound offormula I having at least one salt-forming group obtainable by one ofthe above-mentioned processes a) to c) into its salt, or converting anobtainable salt into the free compound or into a different salt and/orseparating mixtures of isomers that may be obtainable and/or convening acompound of formula I according to the invention into a differentcompound of formula I according to the invention.

Functional groups in starting materials the reaction of which is to beavoided, especially carboxy, amino, hydroxy and mercapto groups, can beprotected by suitable protecting groups (conventional protecting groups)which are customarily used in the synthesis of peptide compounds, andalso in the synthesis of cephalosporins and penicillins as well asnucleic acid derivatives and sugars. Those protecting groups may alreadybe present in the precursors and are intended to protect the functionalgroups in question against undesired secondary reactions, such asacylation, etherification, esterification, oxidation, solvolysis, etc..In certain cases the protecting groups can additionally cause thereactions to proceed selectively, for example stereoselectively. It ischaracteristic of protecting groups that they can be removed easily,i.e. without undesired secondary reactions taking place, for example bysolvolysis, reduction, photolysis, and also enzymatically, for exampleunder physiological conditions. Protecting groups may also be present inthe end products, however. Compounds of formula I having protectedfunctional groups may have greater metabolic stability orpharmacodynamic properties that are better in some other way than thecorresponding compounds having free functional groups.

The protection of functional groups by such protecting groups, theprotecting groups themselves and the reactions for their removal aredescribed, for example, in standard works such as J. F. W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London and NewYork 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis",Wiley, New York 1981, in "The Peptides", Volume 3 (E. Gross and J.Meienhofer, eds.), Academic Press, London and New York 1981, in"Methoden der organischen Chemie", Houben-Weyl, 4th edition, Volume15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H.Jescheit, "Aminosauren, Peptide, Proteine" ("Amino acids, peptides,proteins"), Verlag Chemie, Weinheim, Deerfield Beach and Basle 1982, andin Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide undDerivate" ("The Chemistry of Carbohydrates: monosaccharides andderivatives"), Georg Thieme Verlag, Stuttgart 1974.

Process variant a) (Formation of the amide bond):

Amino-protecting groups X₁ are, for example, acyl groups other thanlower alkanoyl, also arylmethyl, lower alkylthio, 2-acyl-loweralk-1-enyl or silyl. The group X₁ -N(X₂)- can also be in the form of anazido group.

Acyl groups other than lower alkanoyl are, for example, halo-loweralkanoyl, for example 2-haloacetyl, such as 2-chloro-, 2-bromo-,2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, unsubstituted orsubstituted, for example halo-, lower alkoxy- or nitro-substituted,benzoyl, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or4-nitrobenzoyl, or lower alkoxycarbonyl that is branched in the1-position of the lower alkyl radical or suitably substituted in the 1-or 2-position, for example tertiary lower alkoxycarbonyl, such astert-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicalswhich are phenyl that is unsubstituted or mono- or poly-substituted, forexample, by lower alkyl, for example tertiary lower alkyl, such astertiary butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such aschlorine, and/or by nitro, for example benzyloxycarbonyl, unsubstitutedor substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl,diphenylmethoxycarbonyl, fluorenylmethoxycarbonyl or substituteddiphenylmethoxycarbonyl, such as di(4-methoxyphenyl)methoxycarbonyl,aroylmethoxycarbonyl wherein the aroyl group is preferably benzoyl thatis unsubstituted or substituted, for example, by halogen, such asbromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl,for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or2-iodo-ethoxycarbonyl, 2-(tri-substituted silyl)-lower alkoxycarbonyl,for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, for example2-trimethylsilylethoxycarbonyl or2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or triarylsilyl-loweralkoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl.

In a 2-acyl-lower alk-1-enyl radical that can be used as anamino-protecting group, acyl is, for example, the corresponding radicalof a lower alkanecarboxylic acid, of a benzoic acid that isunsubstituted or substituted, for example, by lower alkyl, such asmethyl or tertiary butyl, lower alkoxy, such as methoxy, halogen, suchas chlorine, and/or by nitro, or especially of a carbonic acidsemiester, such as a carbonic acid lower alkyl semiester. Correspondingprotecting groups are especially 1-lower alkanoyl-prop-1-en-2-yl, forexample 1-acetyl-prop-1-en-2-yl, or lower alkoxycarbonyl-prop-1-en-2-yl,for example 1-ethoxy-carbonyl-prop-1-en-2-yl.

A silylamino group is, for example, a tri-lower alkylsilylamino group,for example trimethylsilylamino. The silicon atom of the silylaminogroup can also be substituted by only two lower alkyl groups, forexample methyl groups, and by the amino group or carboxy group of asecond molecule of formula I. Compounds having such protecting groupscan be prepared, for example, using dimethylchlorosilane as silylatingagent.

An amino group can also be protected by conversion into the protonatedform; suitable corresponding anions are especially those of stronginorganic acids, such as sulfuric acid, phosphoric acid or hydrohalicacids, for example the chlorine or bromine anion, or of organic sulfonicacids, such as p-toluenesulfonic acid.

Preferred amino-protecting groups X₁ are acyl radicals of carbonic acidsemiesters, such as lower alkoxycarbonyl, especiallytert-butyloxycarbonyl or fluorenylmethoxycarbonyl, unsubstituted orlower alkyl-, lower alkoxy-, nitro- and/or halo-substituted α-phenyl- orα,α-diphenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl,p-nitrobenzyloxy-carbonyl or diphenylmethoxycarbonyl, or 2-halo-loweralkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, also trityl orformyl.

Hydroxy-protecting groups X₃ are, for example, acyl groups, for examplelower alkanoyl that is substituted by halogen, such as chlorine, forexample 2,2-dichloroacetyl, or especially acyl radicals of a carbonicacid semiester mentioned for protected amino groups. A preferredhydroxy-protecting group is, for example, 2,2,2-trichloroethoxycarbonyl,4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. A furthersuitable hydroxy-protecting group X₃ is tri-lower alkylsilyl, forexample trimethylsilyl, triisopropylsilyl or dimethyl-tert-butylsilyl, areadily removable etherifying group, for example an alkyl group, such astertiary lower alkyl, for example tertiary butyl, an oxa- or athia-aliphatic or -cycloaliphatic, especially 2-oxa- or 2-thia-aliphaticor -cycloaliphatic, hydrocarbon radical, for example 1-loweralkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, for examplemethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl,1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cycloalkylhaving from 5 to 7 ring atoms, for example 2-tetrahydrofuryl or2-tetrahydropyranyl, or a corresponding thia analogue, and also1-phenyl-lower alkyl, for example benzyl, diphenylmethyl or trityl,wherein the phenyl radicals can be substituted, for example, by halogen,for example chlorine, lower alkoxy, for example methoxy, and/or bynitro.

Bivalent protecting groups formed by X₂ and X₃ together are, forexample, methylene groups substituted by one or two alkyl radicals andare accordingly unsubstituted or substituted alkylidene, such as loweralkylidene, for example isopropylidene, cycloalkylidene, such ascyclohexylidene, also carbonyl or benzylidene.

If X₄ is reactively etherified or esterified hydroxy, the terminal group--(═O)--X₄ is a reactively functionally modified carboxylic acidfunction and is, for example, in the form of an activated ester oranhydride. The reactive acid derivatives can also be formed in situ.

Such activated esters of compounds of formula II are especially estersunsaturated at the linking carbon atom of the esterifying radical, forexample of the vinyl ester type, such as vinyl esters (obtainable, forexample, by transesterification of a corresponding ester with vinylacetate; activated vinyl ester method), carbamoyl esters (obtainable,for example, by treatment of the corresponding acid with an isoxazoliumreagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinylesters (obtainable, for example, by treatment of the corresponding acidwith a lower alkoxyacetylene; ethoxyacetylene method), or esters of theamidino type, such as N,N'-disubstituted amidino esters (obtainable, forexample, by treatment of the corresponding acid with a suitableN,N'-disubstituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide; carbodiimide method), orN,N-disubstituted amidino esters (obtainable, for example, by treatmentof the corresponding acid with an N,N-disubstituted cyanamide; cyanamidemethod), suitable aryl esters, especially phenyl esters suitablysubstituted by electron-attracting substituents (obtainable, forexample, by treatment of the corresponding acid with a suitablysubstituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol,2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or4-phenyldiazophenol, in the presence of a condensation agent, such asN,N'-dicyclohexylcarbodiimide; activated aryl esters method),cyanomethyl esters (obtainable, for example, by treatment of thecorresponding acid with chloroacetonitrile in the presence of a base;cyanomethyl esters method), thioesters, especially unsubstituted orsubstituted, for example nitro-substituted, phenylthio esters(obtainable, for example, by treatment of the corresponding acid withunsubstituted or substituted, for example nitro-substituted,thiophenols, inter alia by the anhydride or carbodiimide method;activated thiol esters method), or especially amino or amido esters(obtainable, for example, by treatment of the corresponding acid with anN-hydroxyamino or N-hydroxyamido compound, for exampleN-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide,N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide,1-hydroxybenzotriazole or3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, for example by theanhydride or carbodiimide method; activated N-hydroxy esters method).Internal esters, for example γ-lactones, can also be used.

Anhydrides of acids of formula II may be symmetric or preferably mixedanhydrides of those acids, for example anhydrides with inorganic acids,such as acid halides, especially acid chlorides (obtainable, forexample, by treatment of the corresponding acid with thionyl chloride,phosphorus pentachloride or oxalyl chloride; acid chloride method),azides (obtainable, for example, from a corresponding acid ester via thecorresponding hydrazide and treatment thereof with nitrous acid; azidemethod), anhydrides with carbonic acid semiesters, for example carbonicacid lower alkyl semiesters (obtainable, for example, by treatment ofthe corresponding acid with chloroformic acid lower alkyl esters or witha 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline; mixedO-alkyl-carbonic acid anhydrides method), or anhydrides withdihalogenated, especially dichlorinated, phosphoric acid (obtainable,for example, by treatment of the corresponding acid with phosphorusoxychloride; phosphorus oxychloride method), anhydrides with otherphosphoric acid derivatives (for example those obtainable withphenyl-N-phenylphosphoramidochloridate) or with phosphorous acidderivatives, or anhydrides with organic acids, such as mixed anhydrideswith organic carboxylic acids (obtainable, for example, by treatment ofthe corresponding acid with an unsubstituted or substituted loweralkane- or phenyl-lower alkane-carboxylic acid halide, for examplephenylacetic acid chloride, pivalic acid chloride or trifluoroaceticacid chloride; mixed carboxylic acid anhydrides method) or with organicsulfonic acids (obtainable, for example, by treatment of a salt, such asan alkali metal salt, of the corresponding acid with a suitable organicsulfonic acid halide, such as a lower alkane- or aryl-, for examplemethane- or p-toluene-sulfonic acid chloride; mixed sulfonic acidanhydrides method) and symmetric anhydrides (obtainable, for example, bycondensation of the corresponding acid in the presence of a carbodiimideor 1-diethylaminopropyne; symmetric anhydrides method).

Preferred starting materials of formula II are compounds of formulaeIIa, IIb and IIc ##STR7## wherein X₁ is an amino-protecting group,especially tert-butyloxycarbonyl,

X₂ together with X₃ is a bivalent protecting group, especially loweralkylidene, such as isopropylidene, and

X₃ in formula IIa is hydrogen or tri-lower alkylsilyl, especiallytert-butyl(dimethyl)silyl, or in formula IIb, together with X₂, is abivalent protecting group, especially lower alkylidene, such asisopropylidene, and

X₄ is hydroxy, lower alkoxy or halogen, such as chlorine.

As mentioned, derivatives of carboxylic acids that are used as acylatingagents may also be formed in situ. For example, N,N'-disubstitutedamidino esters may be formed in situ by reacting a mixture of the acidused as acylating agent and the starting material of formula III in thepresence of a suitable N,N'-disubstituted carbodiimide, for exampleN,N'-cyclohexylcarbodiimide. In addition, amino or amido esters of theacids used as acylating agents may be formed in the presence of thestarting material of formula III to be acylated, by reacting a mixtureof the corresponding acid and amino starting materials in the presenceof an N,N'-disubstituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide, and of an N-hydroxyamine orN-hydroxyamide, for example N-hydroxysuccinimide, where appropriate inthe presence of a suitable base, for example 4-dimethylamino-pyridine.

The condensation to form an amide bond can be carried out in a mannerknown per se, for example as described in standard works, such asHouben-Weyl, "Methoden der organischen Chemie", 4th edition, Volume15/II (1974), Volume IX (1955), Volume E 11 (1985), Georg Thieme Verlag,Stuttgart, "The Peptides" (E. Gross and J. Meienhofer, eds.), Volumes 1and 2, Academic Press, London and New York, 1979/1980, or M. Bodansky,"Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.

The condensation of a free carboxylic acid with the corresponding aminecan be carried out preferably in the presence of one of the customarycondensation agents. Customary condensation agents are, for example,carbodiimides, for example diethyl-, dipropyl-,N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or especiallydicyclohexylcarbodiimide, also suitable carbonyl compounds, for examplecarbonyldiimidazole, 1,2-oxazolium compounds, for example2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,also activated phosphoric acid derivatives, for examplediphenylphosphoryl azide, diethylphosphoryl cyanide,phenyl-N-phenylphosphoromidochloridate,bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride or1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate.

If desired, an organic base may be added, for example a tri-loweralkylamine having bulky radicals, for example ethyldiisopropylamine,and/or a heterocyclic base, for example pyridine, N-methylmorpholine orpreferably 4-dimethylaminopyridine.

The condensation of activated esters, reactive anhydrides or reactivecyclic amides with the corresponding amines is customarily carried outin the presence of an organic base, for example simple tri-loweralkylamines, for example triethylamine or tributylamine, or one of theabove-mentioned organic bases. If desired, a condensation agent mayadditionally be used, for example as described for free carboxylicacids.

The condensation of acid anhydrides with amines can be effected, forexample, in the presence of inorganic carbonates, for example ammoniumor alkali metal carbonates or hydrogen carbonates, such as sodium orpotassium carbonate or hydrogen carbonate (usually together with asulfate).

Carboxylic acid chlorides, for example the chlorocarbonic acidderivatives derived from the acid of formula II, are condensed with thecorresponding amines preferably in the presence of an organic amine, forexample the above-mentioned tri-lower alkylamines or heterocyclic bases,where appropriate in the presence of a hydrogen sulfate.

The condensation is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example formamide or dimethylformamide, ahalogenated hydrocarbon, for example methylene chloride, carbontetrachloride or chlorobenzene, a ketone, for example acetone, a cyclicether, for example tetrahydrofuran, an ester, for example ethyl acetate,or a nitrile, for example acetonitrile, or in a mixture thereof, asappropriate at reduced or elevated temperature, for example in atemperature range of from approximately -40° C. to approximately +100°C., preferably from approximately -10° C. to approximately +50° C., andin the case where arylsulfonyl esters are used also at approximatelyfrom +100° C. to +200° C., and without an inert gas or under an inertgas atmosphere, for example a nitrogen or argon atmosphere.

Aqueous, for example alcoholic, solvents, for example ethanol, oraromatic solvents, for example benzene or toluene, may also be used.When alkali metal hydroxides are present as bases, acetone can also beadded where appropriate.

The condensation can also be carded out in accordance with the techniqueknown as solid-phase synthesis which originates from R. Merrifield andis described, for example, in Angew. Chem. 97, 801-812 (1985),Naturwissenschaften 71, 252-258 (1984) or in R. A. Houghten, Proc. Natl.Acad. Sci. U.S.A. 82, 5131-5135 (1985).

A preferred variant of that process is carried out by reacting, as theactivated ester, an internal ester (γ-lactone) derived from thecarboxylic acid of formula I and having the formula IIc ##STR8## whereinX is methylene, with the compound of formula III, free functional groupspresent in the reactants, with the exception of the groups participatingin the reaction, being if desired, as stated above, in protected formand any protecting groups being removed as described above. The openingof the lactone ring with the formation of the amide bond is carried outunder the conditions described above, optionally in the presence of asuitable catalyst. In particular, a γ-lactone IIc may be reacted with aprimary amine III without a solvent or in the presence of a polarsolvent, for example a lower alcohol, such as methanol or ethanol, apolar ether, such as tetrahydrofuran or dioxane, a nitrile, such asacetonitrile, an amide, such as dimethylformamide,N,N-dimethylacetamide, N-methyl-pyrrolidone or hexamethylphosphoric acidtriamide, a urea, for example N,N'-dimethyl-N,N'-propylenylurea, a loweralkoxy-lower alkanol, for example diethylene glycol mono-methyl ether,in dimethyl sulfoxide or in a mixture of the mentioned solvents or in amixture of one or more of the mentioned solvents with water, attemperatures of from room temperature to 150° C., preferablyapproximately from 20° C. to 100° C., and in the presence of a catalyst,such as 2-hydroxypyridine and/or triethylamine, the comments made aboveapplying in respect of the protecting groups.

In another preferred variant of that process the starting material usedis a compound of formula IIb wherein X is methylene, which is reactedwith the reactant of formula III in the presence of a cyanophosphonicacid diester, for example cyanophosphonic acid diethyl ester, and atertiary organic amine, such as a tri-lower alkylamine, for exampletrimethyl-amine, and in a polar solvent, for example a nitrile, such asacetonitrile, an amide, such as dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone or hexamethyl-phosphoric acidtriamide, a urea, for example N,N'-dimethyl-N,N'-propylenylurea, a loweralkoxy-lower alkanol, for example diethylene glycol monomethyl ether, indimethyl sulfoxide or in a mixture of the mentioned solvents or in amixture of one or more of the mentioned solvents with water, attemperatures of from -30° C. to 100° C., preferably from 20° C. to 80°C., the comments made above applying in respect of the protectinggroups.

Starting materials of formula II can be prepared, for example, byreacting a compound of formula VI ##STR9## wherein X₅ is free orreactively esterified hydroxy, especially halogen, such as bromine, witha compound of formula VII ##STR10## in the resulting compound of formulaVIII ##STR11## hydrolysing the 4-benzyl-2-oxo-oxazolidin-1-ylcarbonylgroup selectively to carboxy, for example by means of lithiumhydroxide/hydrogen peroxide; reducing the carboxy group tohydroxymethyl, for example by means of sodium borohydride/iodine intetrahydrofuran; halogenating the hydroxymethyl group, for example withN-bromosuccinimide/triphenyl-phosphine in dichloromethane, and reactingthe reaction product of formula IX ##STR12## wherein X₁₂ is halomethyl,with a compound of formula X ##STR13## wherein R₁₀ and R₁₁ are identicalor different lower alkoxy groups; hydrolysing the resulting compound offormula XI ##STR14## wherein R₁, R₂, R₃, R₄ and R₅ are as defined aboveand R₁₀ and R₁₁ are identical or different lower alkoxy groups;protecting the resulting compound of formula XII ##STR15## at the aminogroup by an amino-protecting group X₁ and, if desired, reacting theresulting compound of formula XIII ##STR16## wherein R₉ is formyl, witha compound of formula XIV ##STR17## wherein M is a metallic, especiallyan alkaline earth metallic, radical, for example a group of the formulaMg-Hal (Hal=halogen, especially bromine), in customary manner, forexample in an ethereal solvent, such as tetrahydrofuran, with cooling,for example in a temperature range of approximately from -80° to 0°; ifdesired temporarily protecting the resulting compound of formula XV##STR18## at the hydroxy group, for example by reaction with a loweralkanoic acid anhydride, especially isobutyric acid anhydride, in thepresence of dimethylaminopyridine in dichloromethane; in the resultingcompound of formula XVI ##STR19## wherein R is hydrogen or ahydroxy-protecting group, such as especially isobutyryl, reducing theazido group to amino, for example by catalytic hydrogenation usingpalladium-on-carbon, it being possible, if desired, for the group --ORto be replaced reductively by hydrogen, and optionally introducing theprotecting group X₁.

For the preparation of compounds of formula IIa, a compound of formulaIIc can be hydrolysed in customary manner with the lactone ring beingopened, for example by treatment with lithium hydroxide in awater-containing solvent, for example in DME/water, optionally thehydroxy-protecting group X₃ can be introduced and, if desired, theterminal carboxy group can be reactively modified.

Starting materials of formula IIb are obtained, for example, by reactinga compound of formula XIII wherein R₉ is formyl with a compound offormula XVII ##STR20## wherein Y₁ is a metallic, especially an alkalineearth metallic, radical, for example of the formula --MgHal wherein Halis bromine, chlorine or iodine, and OR is etherified hydroxy, such asunsubstituted or substituted benzyloxy, to form the correspondingcompound of formula XVIII ##STR21## protecting that compound at theamino and hydroxy groups, for example by a bivalent protecting group--X₂ --X₃ --, such as lower alkylidene, especially isopropylidene; inthe compound of formula XIX thus protected ##STR22## freeing theterminal hydroxy group reductively and converting the terminalhydroxy-methyl group into formyl, for example by treatment withN-methylmorpholine-N-oxide and tetrabutylammonium perruthenate inchloroform, and oxidising the resulting aldehyde to the acid incustomary manner, for example by treatment with potassium permanganate,or oxidising the resulting terminal alcohol directly to the acid bysuitable measures, for example by treatment with sodium iodate/rutheniumchloride, and in each case, if desired, reactively modifying the carboxyfunction.

Process variant b) (Reduction of lower alkylidene or aryl-loweralkylidene R'₇ to lower alkyl or aryl-lower alkyl R₇).

In a starting material of formula IV, functional groups that are not toparticipate in the reaction are protected by suitable protecting groupsmentioned under a).

Hydrogenation agents suitable for the hydrogenation of the olefinicdouble bond are those which under the reaction conditions of the processreduce the double bond selectively or more rapidly than the amide bondspresent in compounds of formula IV.

Especially suitable are hydrogenation agents such as hydrogen in thepresence of suitable catalysts.

Catalysts suitable for hydrogenation are metals, for example nickel,iron, cobalt or ruthenium, or noble metals or their oxides, such aspalladium or rhodium or their oxides, optionally supported on a suitablecarrier, such as barium sulfate, aluminium oxide or active carbon, or inthe form of skeleton catalysts, for example Raney nickel, but especiallyhomogeneous or heterogeneous metal- or noble metal-ligand complexes,more especially those which produce the configuration at the carbon atomcarrying the group R₄ desired in each particular case.

Such catalysts are especially complexes of ruthenium or ruthenium salts,such as Ru(II) halides, such as RuCl₂, Ru₂ Cl₂ or RuHCl, optionallyhalogenated Ru(II) lower alkanoylates, such as Ru(OAc)₂ orRu(OOC--CF₃)₂, with (S)-bis(2,2'-diphenylphosphino)-1,1'-bi-naphthyl(S-BINAP) or derivatives thereof which contain instead of phenylsubstituted phenyl radicals, such as p-tolyl or p-methoxyphenyl, andalso ruthenium complexes with(S)-bis(2,2'-diphenylphosphino)-5,5'-dimethyl-diphenyl and the like.Hydrogenation with complexes of that type is preferably carried out inalcohols, such as lower alkanols, or alkyl halides, such as methylenechloride, in a pressure range of approximately from 1 to 100 bar,preferably from 20 to 30 bar, and in a temperature range ofapproximately from 10° to 80° C., preferably from 15° to 25° C.

Other solvents customarily used for catalytic hydrogenation are polarorganic or inorganic solvents, for example water, alcohols, esters,dioxane, glacial acetic acid or mixtures of those solvents. Thehydrogenation is carried out at temperatures of from 0° C. to 250° C.,preferably from room temperature to about 100° C. and at hydrogenpressures of from 1 to 200 bar. Hydrogenation methods will be found, forexample, in "Organikum, organisch-chemisches Grundpraktikum", 17threvised edition, VEB Deutscher Verlag der Wissenschaften, Berlin 1988.

Carboxylic acid amides of formula IV are obtained, for example, bycondensing an aldehyde of formula XIII ##STR23## wherein R₉ is formyl,in customary manner with a suitable metallated amide compound, forexample obtainable by reaction of a compound of formula XX ##STR24##with butyllithium and chlorotitanium triisopropyl oxide.

Process variant c) (Reduction of the azido group):

In starting materials of formula V, functional groups that are not toparticipate in the reaction are protected by one of the protectinggroups mentioned under Process a).

Reducing agents suitable for the reduction of the azido group are thosewhich under the reaction conditions of the process reduce an optionallyfunctionalised hydroxy group or azido group selectively or more rapidlythan the amide groups present in compounds of formula I.

The reduction is preferably carried out with hydrogen in the presence ofsuitable heavy metal catalysts, for example Raney nickel or platinum orpalladium catalysts, for example platinum or palladium on active carbon.

Intermediates of formula V can be prepared, for example, by reactingE-1,4-dibromobut-2-ene first with a compound of formula VII ##STR25##and then with a compound of formula XXI ##STR26## to form thecorresponding compound of formula XXII ##STR27## converting thatcompound, for example by treatment with a customary halogenating agent,such as elemental halogen, especially bromine or iodine, or preferablywith an N-halosuccinimide, especially N-bromosuccinimide, in1,2-dimethoxyethane (DME), into the corresponding compound of formulaXXIII ##STR28## wherein Hal is halogen; separating the desired isomer inrespect of R₅ and R₇ and in that isomer replacing the halogen atom byazido, for example by treatment with tetrabenzyl-ammonium azide intoluene, and in the resulting compound of formula XXIV ##STR29## whereinR₅ and R₇ are as defined above and Bz is benzyl, hydrolysing the4-benzyl-2-oxo-oxazolidin-1-ylcarbonyl group selectively to carboxy, forexample by treatment with an alkali metal hydroxide in the presence of abasic hydrolysing agent, especially lithium hydroxide in the presence ofhydrogen peroxide; re-closing, using an acid catalyst, a lactone ringwhich may have been opened; in the resulting compound of formula XXV##STR30## wherein R₉ is carboxy, converting the carboxy group intoformyl, for example by conversion into the acid chloride by means ofoxalyl chloride and subsequent reduction of the chlorocarbonyl group,for example with sodium tri-tert-butyloxyaluminium hydride intetrahydrofuran; reacting the resulting compound of formula XXV whereinR₉ is then formyl with a compound of formula XIV ##STR31## wherein M isa metallic, especially an alkaline earth metallic, radical, for examplea group of the formula Mg-Hal (Hal=halogen, especially bromine), incustomary manner, for example in an ethereal solvent, such astetrahydrofuran, with cooling, for example in a temperature range ofapproximately from -80° to 0° C.; if desired etherifying or, especially,esterifying the resulting compound of formula XV ##STR32## at thehydroxy group, for example temporarily protecting the hydroxy group byreaction with a lower alkanoic acid anhydride, especially isobutyricacid anhydride, in the presence of dimethylaminopyridine indichloromethane; reacting the resulting compound of formula XVI##STR33## wherein the group --OR is a free or esterified or etherifiedhydroxy group, with R preferably being a hydroxy-protecting group, suchas especially isobutyryl, in customary manner, for example as indicatedunder Process variant a), with an amine of formula III

    H.sub.2 N--R.sub.8                                         (III),

wherein R₈ has one of the meanings given under formula I, and, ifdesired, freeing hydroxymethyl from the group --OR or replacing thegroup --OR reductively by hydrogen.

The removal of protecting groups that are not constituents of thedesired end product of formula I, for example carboxy-, amino-, hydroxy-and/or mercapto-protecting groups, which may be carried out subsequentto the process variants described above, is effected in a manner knownper se, for example by means of solvolysis, especially hydrolysis,alcoholysis or acidolysis, or by means of reduction, especiallyhydrogenolysis or chemical reduction, as well as photolysis, asappropriate stepwise or simultaneously, it being possible also to useenzymatic methods. The removal of the protecting groups is described,for example, in the standard works mentioned hereinabove in the sectionrelating to protecting groups.

For example, protected carboxy, for example tertiary loweralkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by atrisubstituted silyl group or in the 1-position by lower alkoxy or bylower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonylcan be converted into free carboxy by treatment with a suitable acid,such as formic acid or trifluoroacetic acid, where appropriate with theaddition of a nucleophilic compound, such as phenol or anisole.Unsubstituted or substituted benzyloxycarbonyl can be freed, forexample, by means of hydrogenolysis, i.e. by treatment with hydrogen inthe presence of a metal hydrogenation catalyst, such as a palladiumcatalyst. In addition, suitably substituted benzyloxycarbonyl, such as4-nitrobenzyloxycarbonyl, can be converted into free carboxy also byreduction, for example by treatment with an alkali metal dithionite,such as sodium dithionite, or with a reducing metal, for example zinc,or a reducing metal salt, such as a chromium(H) salt, for examplechromium(II) chloride, customarily in the presence of ahydrogen-yielding agent that, together with the metal, is capable ofproducing nascent hydrogen, such as an acid, especially a suitablecarboxylic acid, such as an unsubstituted or substituted, for examplehydroxy-substituted, lower alkanecarboxylic acid, for example aceticacid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid,mandelic acid, 4-chloromandelic acid or tartaric acid, or in thepresence of an alcohol or thiol, water preferably being added. Bytreatment with a reducing metal or metal salt, as described above,2-halo-lower alkoxycarbonyl (where appropriate after conversion of a2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-loweralkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted intofree carboxy. Aroylmethoxycarbonyl can be cleaved also by treatment witha nucleophilic, preferably salt-forming, reagent, such as sodiumthiophenolate or sodium iodide. 2-(Tri-substituted silyl)-loweralkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, canbe converted into free carboxy also by treatment with a salt ofhydrofluoric acid that yields the fluoride anion, such as an alkalimetal fluoride, for example sodium or potassium fluoride, whereappropriate in the presence of a macrocyclic polyether ("crown ether"),or with a fluoride of an organic quaternary base, such as tetra-loweralkyl-ammonium fluoride or tri-lower alkylarylammonium fluoride, forexample tetraethylammonium fluoride or tetrabutylammonium fluoride, inthe presence of an aprotic, polar solvent, such as dimethyl sulfoxide orN,N-dimethylacetamide. Carboxy protected in the form of organicsilyloxycarbonyl, such as tri-lower alkylsilyloxycarbonyl, for exampletrimethylsilyloxycarbonyl, can be freed in customary manner bysolvolysis, for example by treatment with water, an alcohol or an acid,or, furthermore, a fluoride, as described above. Esterified carboxy canalso be freed enzymatically, for example by means of esterases orsuitable peptidases.

A protected amino group is freed in a manner known per se and, accordingto the nature of the protecting groups, in various ways, preferably bysolvolysis or reduction. 2-Halo-lower alkoxycarbonylamino (whereappropriate after conversion of a 2-bromo-lower alkoxycarbonylaminogroup into a 2-iodo-lower alkoxycarbonylamino group),aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can becleaved, for example, by treatment with a suitable reducing agent, suchas zinc in the presence of a suitable carboxylic acid, such as aqueousacetic acid. Aroylmethoxycarbonylamino can be cleaved also by treatmentwith a nucleophilic, preferably salt-forming, reagent, such as sodiumthiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment withan alkali metal dithionite, for example sodium dithionite. Unsubstitutedor substituted diphenylmethoxycarbonylamino, tert-loweralkoxycarbonylamino or 2-(tri-substituted silyl)-loweralkoxycarbonylamino, such as 2-tri-lower alkylsilyl-loweralkoxycarbonylamino, can be cleaved by treatment with a suitable acid,for example formic or trifluoroacetic acid; unsubstituted or substitutedbenzyloxycarbonylamino can be cleaved, for example, by means ofhydrogenolysis, i.e. by treatment with hydrogen in the presence of asuitable hydrogenation catalyst, such as a palladium catalyst;unsubstituted or substituted triarylmethylamino or formylamino can becleaved, for example, by treatment with an acid, such as a mineral acid,for example hydrochloric acid, or an organic acid, for example formic,acetic or trifluoroacetic acid, where appropriate in the presence ofwater; and an amino group protected in the form of silylamino can befreed, for example, by means of hydrolysis or alcoholysis. An aminogroup protected by 2-haloacetyl, for example 2-chloroacetyl, can befreed by treatment with thiourea in the presence of a base, or with athiolate salt, such as an alkali metal thiolate of thiourea, andsubsequent solvolysis, such as alcoholysis or hydrolysis, of theresulting condensation product. An amino group protected by2-(tri-substituted silyl)-lower alkoxycarbonyl, such as 2-tri-loweralkylsilyl-lower alkoxycarbonyl, can be converted into the free aminogroup also by treatment with a salt of hydrofluoric acid that yieldsfluoride anions, as indicated above in connection with the freeing of acorrespondingly protected carboxy group. Likewise, silyl, such astrimethylsilyl, bonded directly to a hetero atom, such as nitrogen, canbe removed using fluoride ions.

Amino protected in the form of an azido group is converted into freeamino, for example, by reduction, for example by catalytic hydrogenationwith hydrogen in the presence of a hydrogenation catalyst, such asplatinum oxide, palladium or Raney nickel, by reduction using mercaptocompounds, such as dithiothreitol or mercaptoethanol, or by treatmentwith zinc in the presence of an acid, such as acetic acid. The catalytichydrogenation is preferably carried out in an inert solvent, such as ahalogenated hydrocarbon, for example methylene chloride, or in water orin a mixture of water and an organic solvent, such as an alcohol ordioxane, at approximately from 20° C. to 25° C., or with cooling orheating.

A hydroxy or mercapto group protected by a suitable acyl group, by atri-lower alkylsilyl group or by unsubstituted or substituted1-phenyl-lower alkyl is freed analogously to a correspondingly protectedamino group. A hydroxy or mercapto group protected by 2,2-dichloroacetylis freed, for example, by basic hydrolysis, and a hydroxy or mercaptogroup protected by tertiary lower alkyl or by a 2-oxa- or2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is removed byacidolysis, for example by treatment with a mineral acid or a strongcarboxylic acid, for example trifluoroacetic acid. Mercapto protected bypyridyldiphenylmethyl can be freed, for example, using mercury(H) saltsat pH 2-6 or by zinc/acetic acid or by electrolytic reduction;acetamidomethyl and isobutyrylamidomethyl can be removed, for example,by reaction with mercury(H) salts at pH 2-6; 2-chloroacetamidomethyl canbe removed, for example, using 1-piperidinothiocarboxamide; andS-ethylthio, S-tert-butylthio and S-sulfo can be cleaved, for example,by thiolysis with thiophenol, thioglycolic acid, sodium thiophenolate or1,4-dithiothreitol. Two hydroxy groups or an adjacent amino and hydroxygroup which are protected together by means of a bivalent protectinggroup, preferably, for example, by a methylene group mono- ordi-substituted by lower alkyl, such as lower alkylidene, for exampleisopropylidene, cyclo-alkylidene, for example cyclohexylidene, orbenzylidene, can be freed by acid solvolysis, especially in the presenceof a mineral acid or a strong organic acid. 2-Halo-lower alkoxycarbonylis also removed using the above-mentioned reducing agents, for example areducing metal, such as zinc, reducing metal salts, such as chromium(II)salts, or using sulfur compounds, for example sodium dithionite orpreferably sodium sulfide and carbon disulfide.

When several protected functional groups are present, if desired theprotecting groups may be so selected that more than one such group canbe removed simultaneously, for example by acidolysis, such as bytreatment with trifluoroacetic acid, or with hydrogen and ahydrogenation catalyst, such as a palladium-on-carbon catalyst.Conversely, the groups may also be so selected that they are not allremoved simultaneously, but rather they are removed in a desiredsequence or only some of them are removed.

In each of the processes mentioned above, the starting compounds mayalso be used in the form of salts, provided that the reaction conditionsallow it.

Compounds of formula I obtainable in accordance with the process can beconverted into different compounds of formula I in customary manner.

For example, in a compound of formula I obtainable in accordance withthe process, hydroxymethyl X can be reduced reductively to methylene,for example by catalytic hydrogenation in the presence ofpalladium-on-carbon.

Futhermore, in a compound of formula I obtainable in accordance with theprocess, a carboxy group in free or reactive form may be esterified oramidated or an esterified or amidated carboxy group may be convertedinto a free carboxy group.

For the esterification or amidation of a carboxy group in a compound offormula I, if desired the free acid can be used or the free acid can beconverted into one of the above-mentioned reactive derivatives andreacted with an alcohol, with ammonia, or with a primary or secondaryamine, or, in the case of esterification, the free acid or a reactivesalt, for example the caesium salt, can be reacted with a reactivederivative of an alcohol. For example the caesium salt of a carboxylicacid can be reacted with a halide or sulfonic acid ester correspondingto the alcohol. The esterification of the carboxy group can also becarried out with other customary alkylating agents, for example withdiazomethane, Meerwein salts or 1-substituted 3-aryltriazenes.

For the conversion of an esterified or amidated carboxy group into thefree carboxy group it is possible to use one of the methods describedabove for the removal of carboxy-protecting groups or, if desired,alkaline hydrolysis in accordance with the reaction conditions mentionedin Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften,Berlin 1988.

In a compound of formula I obtainable in accordance with the process, anesterified carboxy group can be converted into an unsubstituted orsubstituted carboxamide group by aminolysis with ammonia or with aprimary or secondary amine, optionally in the presence of a suitablecondensation agent or catalyst. The aminolysis can be carried out inaccordance with the reaction conditions mentioned for such reactions inOrganikum, 15th edition, VEB Deutschcr Verlag der Wissenschaften, Berlin(East) 1976.

A free amino group present in a compound of formula I obtainable inaccordance with the process can be acylated or alkylated, for example tointroduce a radical R₆ other than hydrogen. The acylation and thealkylation can be carded out in accordance with one of the methodsmentioned for protecting groups or according to one of the processesmentioned in Organikum, 17th edition, VEB Deutscher Verlag derWissenschaften, Berlin (East) 1988.

Furthermore, a free hydroxy group present in a compound of formula Iobtainable in accordance with the process, for example as a constituentof the radical R₈, can be acylated. The acylation can be carried outwith acylating reagents in accordance with one of the methods mentionedfor protecting groups or according to one of the processes mentioned inOrganikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin(East) 1988.

In a compound of formula I obtainable in accordance with the process itis also possible to obtain from a sulfide the corresponding sulfoxide orsulfone, that is to say to oxidise a thio group to a sulfinyl orsulfonyl group or a sulfinyl group to sulfonyl, and also to oxidisethiomorpholino to S-oxy- or S,S-dioxy-thiomorpholino.

The oxidation to the sulfone can be carried out with most of thecustomary oxidising agents. It is especially preferable to use oxidisingagents that oxidise the thio group or the sulfide sulfur selectively inthe presence of other functional groups, for example amino or hydroxygroups, of the compound of formula I in question, for example aromaticor aliphatic peroxycarboxylic acids, for example peroxybenzoic acid,monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid, performicacid or trifluoroperacetic acid. The oxidation with peroxycarboxylicacids is carried out in suitable solvents customarily used for thatpurpose, for example chlorinated hydrocarbons, for example methylenechloride or chloroform, ethers, such as diethyl ether, esters, such asethyl acetate or the like, at temperatures of from -78° C. to roomtemperature, for example from -20° C. to +1 0° C., preferably about 0°C. The peroxycarboxylic acid can also be formed in situ, for examplewith hydrogen peroxide in acetic acid or formic acid that optionallycontains acetic anhydride, for example with 30% or 90% hydrogen peroxidein acetic acid/acetic anhydride. Other peroxo compounds are alsosuitable, for example potassium peroxomonosulfate in lower alkanol/watermixtures, for example methanol/water or ethanol/water, or in aqueousacetic acid at temperatures of from -70° C. to +30° C., for example from-20° C. to room temperature, and also sodium metaperiodate in methanolor methanol/water mixtures at temperatures of from 0° C. to 50° C., forexample about room temperature. If stoichiometric amounts of thementioned oxidising agents arc used it is also possible to obtain thecorresponding sulfoxides.

If desired, it is possible by reduction of a sulfonyl group or a sulfoneradical in an obtainable compound of formula I to obtain thecorresponding thio compound or the corresponding sulfide, for examplewith diisobutylaluminium hydride in ether or tetrahydrofuran.

In compounds of formula I it is also possible to replace hydroxy R₁, R₂,R₃ and/or R₄ by one of the etherified hydroxy groups mentioned underformula I by reacting the corresponding compound of formula I whereinR₁, R₂, R₃ and/or R₄ is hydroxy in customary manner, for example in thepresence of a basic condensation agent, with a compound of theformula(e) R'₁ --Y, R'₂ --Y, R'₃ --Y and/or R'₄ --Y wherein R'₁ is loweralkyl or free or esterified or amidated carboxy-lower alkyl, R'₂ islower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-loweralkyl, cycloalkoxy-lower alkyl, optionally lower alkanoylated,halogenated or sulfonylated hydroxy-lower alkyl, oxo-lower alkyl, loweralkyl, lower alkenyl, cycloalkoxy-lower alkyl, lower alkoxy-lower alkyl,lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkyl, loweralkenyloxy-lower alkyl, lower alkenyloxy-lower alkyl, loweralkanoyl-lower alkyl, optionally S-oxidised lower alkyl-thio-loweralkyl, lower alkylthio-(hydroxy)-lower alkyl, aryl-lower alkyl,optionally hydrogenated heteroaryl-lower alkyl, optionally hydrogenatedheteroarylthio-lower alkyl, cyano-lower alkyl or free or esterified oramidated carboxy-lower alkyl, R'₃ is lower alkyl, lower alkoxy-loweralkyl, hydroxy-lower alkyl, aryl-lower alkyl, halogenated lower alkyl,cyano-lower alkyl or free or esterified or amidated carboxy-lower alkyl,and R'₄ is lower alkyl, and Y is reactive esterified hydroxy, especiallyhydroxy esterified by a mineral acid, by sulfuric acid or by an organicsulfonic acid, such as halogen, preferably chlorine, bromine or iodine,groups of the formula O--SO₂ --O--R'_(A), or lower alkanesulfonyloxy orunsubstituted or substituted benzenesulfonyloxy, especially methane-,ethane-, benzene-, p-toluene- or p-bromobenzene-sulfonyl. The reactionis, as mentioned, preferably carried out in the presence of a basiccondensation agent, such as an alkali metal carbonate, for examplepotassium carbonate, in an inert solvent, such as a lower alkanol, suchas methanol, ethanol, butanol, tert-butanol or especially amyl alcohol,advantageously at elevated temperature, for example in a temperaturerange of approximately from 40° to 140° C., if necessary with removal ofthe resulting water of reaction by distillation, for example byazeotropic distillation.

It is also possible for salts of compounds of formula I obtainable inaccordance with the process to be converted in a manner known per seinto the free compounds, for example by treatment with a base, such asan alkali metal hydroxide, a metal carbonate or metal hydrogencarbonate, or ammonia, or another of the salt-forming bases mentioned atthe beginning, or with an acid, such as a mineral acid, for example withhydrochloric acid, or another of the salt-forming acids mentioned at thebeginning.

Resulting salts can be converted into different salts in a manner knownper se: acid addition salts, for example, by treatment with a suitablemetal salt, such as a sodium, barium or silver salt, of a different acidin a suitable solvent in which an inorganic salt being formed isinsoluble and is therefore eliminated from the reaction equilibrium, andbasic salts by freeing of the free acid and conversion into a saltagain.

The compounds of formula I, including their salts, may also be obtainedin the form of hydrates or may include the solvent used forcrystallisation.

As a result of the close relationship between the novel compounds infree form and in the form of their salts, hereinabove and hereinbelowany reference to the free compounds and their salts is to be understoodas including also the corresponding salts and free compounds,respectively, as appropriate and expedient.

Stereoisomeric mixtures, that is to say mixtures of diastereoisomersand/or enantiomers, such as, for example, racemic mixtures, can beseparated into the corresponding isomers in a manner known per se bysuitable separating processes. For example, mixtures of diastereoisomerscan be separated into the individual diastereoisomers by fractionalcrystallisation, chromatography, solvent partition etc.. Racemates canbe separated from one another, after conversion of the optical antipodesinto diastereoisomers, for example by reaction with optically activecompounds, for example optically active acids or bases, bychromatography on column materials charged with optically activecompounds or by enzymatic methods, for example by selective reaction ofonly one of the two enantiomers. This separation can be carried outeither at the stage of one of the starting materials or with thecompounds of formula I themselves.

In a compound of formula I the configuration at individual chiralitycentres can be selectively reversed. For example, the configuration ofasymmetric carbon atoms that carry nucleophilic substituents, such asamino or hydroxy, can be reversed by second order nucleophilicsubstitution, optionally after conversion of the bonded nucleophilicsubstituent into a suitable nucleofugal leaving group and reaction witha reagent introducing the original substituent, or the configuration atcarbon atoms having hydroxy groups can be reversed by oxidation andreduction, analogously to European Patent Application EP-A-0 236 734.

Also advantageous is the reactive functional modification of the hydroxygroup and the subsequent replacement thereof by hydroxy with theconfiguration being reversed. For that purpose, the amino and hydroxygroups shown in formula I are bridged by a bivalent group, especiallycarbonyl, there being obtained a compound of formula XXVI ##STR34##which can be cleaved again by treatment with thionyl chloride with theconfiguration being reversed.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage is used as startingmaterial and the remaining steps are carried out or the process isinterrupted at any stage or a starting material is formed under thereaction conditions or is used in the form of a reactive derivative orsalt, or a compound obtainable in accordance with the process of theinvention is formed under the process conditions and further processedin situ. It is preferable to use those starting materials which resultin the compounds described above as being very preferred or veryespecially preferred.

The invention relates also to novel starting materials, which have beendeveloped specifically for the preparation of the compounds according tothe invention, especially the group of starting materials resulting inthe compounds of formula I described at the beginning as beingpreferred, to processes for their preparation and to their use asintermediates.

This relates to compounds of formula II which, as mentioned, aresuitable as intermediates for the preparation of compounds of formula I.

The invention relates accordingly also to compounds of formula II##STR35## wherein R₁ is hydrogen, hydroxy, lower alkoxy, cycloalkoxy,lower alkoxy-lower alkoxy or free or esterified or amidatedcarboxy-lower alkoxy,

R₂ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy-lower alkyl, loweralkoxy-lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy,optionally lower alkanoylated, halogenated or sulfonylated hydroxy-loweralkoxy; amino-lower alkyl that is unsubstituted or substituted by loweralkyl-, by lower alkanoyl- and/or by lower alkoxy-carbonyl; amino-loweralkoxy that is substituted by lower alkyl, by lower alkanoyl and/or bylower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, cycloalkoxy, loweralkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkoxy, loweralkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-loweralkoxy, lower alkenyloxy-lower alkyl, lower alkanoyl-lower alkoxy,optionally S-oxidised lower alkylthio-lower alkoxy, loweralkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, cyano-lower alkoxy,free or esterified or amidated carboxy-lower alkoxy or free oresterified or amidated carboxy-lower alkyl,

R₃ is optionally halogenated lower alkyl, lower alkoxy-lower alkyl,cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally S-oxidisedlower alkylthio-lower alkyl, optionally hydrogenated heteroaryl-loweralkyl, optionally hydrogenated heteroarylthio-lower alkyl; amino-loweralkyl that is unsubstituted or N-mono- or N,N-di-lower alkylated,N-lower alkanoylated or N-lower alkanesulfonylated or N,N-disubstitutedby lower alkylene, by unsubstituted or N'-lower alkylated or N'-loweralkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionallyS-oxidised thia-lower alkylene; cyano-lower alkyl, free or esterified oramidated carboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy,cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy,hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated loweralkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally hydrogenatedheteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted orN-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-loweralkanesulfonylated or substituted by lower alkylene, by unsubstituted orN'-lower alkylated or N'-lower alkanoylated aza-lower alkylene, byoxa-lower alkylene or by optionally S-oxidised thia-lower alkylene;cyano-lower alkoxy or free or esterified or amidated carboxy-loweralkoxy, or together with R₄ is lower alkylenedioxy or a fused-on benzoor cyclohexeno ring,

R₄ together with R₃ is lower alkylenedioxy or a fused-on benzo orcyclohexeno ring, or is hydrogen, hydroxy or lower alkoxy,

X is methylene or hydroxymethylene,

R₅ is lower alkyl or cycloalkyl,

R₇ is lower alkyl or aryl-lower alkyl,

X₁ is an amino-protecting group,

X₂ is hydrogen or together with X₃ is a bivalent protecting group,

X₃ is hydrogen, a hydroxy-protecting group or together with X₂ is abivalent protecting group or together with X₄ is a direct bond, and

X₄ is free or reactively etherified or esterified hydroxy or togetherwith X₃ is a direct bond,

and to the salts thereof, to processes for the preparation thereof andto the use thereof as intermediates for the preparation of medicinalactive ingredients, especially of formula I.

In the compounds of formula II prepared according to the invention thevariables R₁, R₂, R₃, R₄, X, R₅ and R₇ are preferably as defined forformula I, and the variables X₁, X₂, X₃ and X₄ are preferably as definedfor formula II.

The invention relates especially to compounds of formula II wherein

R₁ is hydrogen, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-loweralkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy,carbamoyl-lower alkoxy or N-mono- or N,N-di-lower alkylcarbamoyl-loweralkoxy,

R₂ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy-lower alkyl, loweralkoxy-lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy, loweralkanoyloxy-lower alkyl, hydroxy-lower alkoxy, halo-(hydroxy)-loweralkoxy, lower alkanesulfonyl-(hydroxy)-lower alkoxy, amino-lower alkyl,lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, loweralkanoylamino-lower alkyl, lower alkoxycarbonyl-amino-lower alkyl,amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkoxycarbonyl-amino-lower alkoxy, oxo-lower alkoxy, lower alkoxy,cycloalkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, loweralkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-loweralkoxy, lower alkoxy-lower alkoxy, lower alkenyloxy-lower alkyl, loweralkanoyl-lower alkoxy, lower alkylthio-lower alkoxy, loweralkane-sulfonyl-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy,aryl-lower alkoxy, thiazolylthio-lower alkoxy or thiazolinylthio-loweralkoxy, imidazolylthio-lower alkoxy, optionally N-oxidisedpyridylthio-lower alkoxy, pyrimidinylthio-lower alkoxy, cyano-loweralkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy,N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy, carboxy-loweralkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl orN-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl,

R₃ is lower alkyl, polyhalo-lower alkyl, lower alkoxy-lower alkyl,cycloalkoxy-lower alkyl, hydroxy-lower alkyl, lower alkylthio-loweralkyl, lower alkanesulfonyl-lower alkyl, optionally partiallyhydrogenated or N-oxidised pyridyl-lower alkyl, thiazolyl-thio-loweralkyl or thiazolinylthio-lower alkyl, imidazolylthio-lower alkyl,optionally N-oxidised pyridylthio-lower alkyl, pyrimidinylthio-loweralkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-loweralkylamino-lower alkyl, lower alkanoyl-amino-lower alkyl, loweralkanesulfonylamino-lower alkyl, polyhalo-loweralkane-sulfonylamino-lower alkyl, pyrrolidino-lower alkyl,piperidino-lower alkyl, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkyl, morpholino-lower alkyl,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothio-morpholino-loweralkyl, cyano-lower alkyl, carboxy-lower alkyl, loweralkoxy-carbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- orN,N-di-lower alkyl-carbamoyl-lower alkyl, cycloalkyl; phenyl or naphthylthat is unsubstituted or mono-, di- or tri-substituted by lower alkyl,lower alkoxy, hydroxy, lower alkylamino, di-lower alkylamino, halogenand/or by trifluoromethyl; hydroxy, lower alkoxy, cyclo-alkoxy, loweralkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy;phenyl-lower alkoxy or naphthyl-lower alkoxy that is unsubstituted ormono-, di- or tri-substituted by lower alkyl, lower alkoxy, hydroxy,lower alkylamino, di-lower alkylamino, halogen and/or bytrifluoromethyl; lower alkoxy, polyhalo-lower alkoxy, loweralkylthio-lower alkoxy, lower alkanesulfonyl-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally partially or fullyhydrogenated heteroarylthio-lower alkoxy, such as thiazolylthio-loweralkoxy or thiazolinylthio-lower alkoxy, imidazolylthio-lower alkoxy,optionally N-oxidised pyridylthio-lower alkoxy, pyrimidinylthio-loweralkoxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkanesulfonylamino-lower alkoxy, polyhalo-loweralkanesulfonylamino-lower alkoxy, pyrrolidino-lower alkoxy,piperidino-lower alkoxy, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkoxy, morpholino-lower alkoxy,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothiomorpholino-loweralkoxy, cyano-lower alkoxy, carboxy-lower alkoxy, loweralkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy or N-mono- orN,N-di-lower alkylcarbamoyl-lower alkoxy, or together with R₄ is loweralkylenedioxy or a fused-on benzo or cyclohexeno ring,

R₄ together with R₃ is lower alkylenedioxy or a fused-on benzo orcyclohexeno ring, or is hydrogen, hydroxy or lower alkoxy,

X is methylene or hydroxymethylene,

R₅ is lower alkyl or cycloalkyl,

R₇ is lower alkyl, or phenyl-lower alkyl that is unsubstituted orsubstituted by lower alkyl, lower alkoxy, hydroxy, halogen, nitro and/orby amino,

X₁ is lower alkoxycarbonyl, or α-phenyl- or α,α-diphenyl-loweralkoxycarbonyl that is unsubstituted or substituted by lower alkyl,lower alkoxy, nitro and/or by halogen, or is 2-halo-loweralkoxycarbonyl,

X₂ is hydrogen or together with X₃ is carbonyl or lower alkylidene,

X₃ is hydrogen, tri-lower alkylsilyl or together with X₂ is carbonyl orlower alkylidene or together with X₄ is a direct bond, and

X₄ is lower alkoxy, phenyl-lower alkoxy or hydroxy or together with X₃is a direct bond,

and the salts thereof.

The invention relates more especially to compounds of formula II wherein

R₁ is hydrogen,

R₂ is lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy,lower alkoxy-lower alkoxy-lower alkyl; phenyl-lower alkoxy that isunsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,halogen, nitro and/or by amino; optionally N-oxidised pyridyl-loweralkoxy, lower alkylthio-lower alkoxy, lower alkane-sulfonyl-loweralkoxy, lower alkanoyl-lower alkoxy, optionally N-oxidised pyridyl-loweralkoxy, cyano-lower alkoxy, carboxy-lower alkoxy, loweralkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy, loweralkylcarbamoyl-lower alkoxy or di-lower alkylcarbamoyl-lower alkoxy,

R₃ is hydrogen, lower alkyl, hydroxy, lower alkoxy or polyhalo-loweralkoxy or together with R₄ is lower alkylenedioxy,

X is methylene or hydroxymethylene,

R₅ is lower alkyl or cycloalkyl,

R₇ is lower alkyl,

X₁ is lower alkoxycarbonyl, or α-phenyl-lower alkoxycarbonyl that isunsubstituted or substituted by lower alkyl, lower alkoxy, nitro and/orby halogen,

X₂ is hydrogen or together with X₃ is lower alkylidene,

X₃ is hydrogen or together with X₂ is lower alkylidene or together withX₄ is a direct bond, and

X₄ is hydroxy or together with X₃ is a direct bond,

and the salts thereof.

The invention relates especially to compounds of formula II wherein atleast one, for example one, two or preferably all, of the asymmetriccarbon atoms of the main chain have the stereochemical configurationshown in formula IId ##STR36## the variables each being as definedabove, and the salts thereof.

The invention relates very especially to compounds of formula IIdwherein

R₁ and R₄ are hydrogen,

R₂ is C₁ -C₄ alkoxy-C₁ -C₄ alkoxy, such as 3-methoxypropyloxy, or C₁ -C₄alkoxy-C₁ -C₄ -alkyl, such as 3-methoxybutyl,

R₃ is C₁ -C₄ alkyl, such as isopropyl or tert-butyl, or C₁ -C₄ alkoxy,such as methoxy,

X is methylene,

R₅ and R₇ are branched C₁ -C₄ alkyl, such as isopropyl, and

X₁ is C₁ -C₇ alkoxycarbonyl, such as tert-butoxycarbonyl,

and the salts thereof.

The invention relates specifically to the compounds of formulae II andIId mentioned in the Examples and the salts thereof.

The process according to the invention for the preparation of compoundsof formula II is as follows:

d) for the preparation of compounds of formula IIc, in a compound offormula XVI ##STR37## wherein R is a hydroxy-protecting group, the azidogroup is reduced to amino and, if desired, hydroxy is freed from thegroup --OR or the group --OR is replaced reductively by hydrogen, andthe protecting group X₁ is introduced, and

e) for the preparation of compounds of formula IIa, a compound offormula IIc is hydrolysed in customary manner, the hydroxy-protectinggroup X₃ is introduced and, if desired, the terminal carboxy group isreactively modified, or

f) for the preparation of compounds of formula IIb, in a compound offormula XIX ##STR38## the terminal hydroxy group is freed reductivelyand the terminal hydroxymethyl group is first converted into formyl incustomary manner, for example as indicated under Process variant a), andthe formyl group formed is oxidised to the acid in customary manner orthe terminal hydroxy group is oxidised directly to the acid, and, ifdesired, the carboxy function is reactively modified, if necessary anyprotecting groups present are removed and, if desired, the compoundobtainable in accordance with the process is converted into a salt or asalt obtainable in accordance with the process is converted into thefree compound or into a different salt and/or mixtures of isomers thatmay be obtainable are separated.

The starting materials of formulae XVI and XIX are prepared, forexample, as indicated under Process variant a).

Compounds of formula II obtainable in accordance with the process can beconverted into different compounds of formula II in customary manner.

For example, in a compound of formula II obtainable in accordance withthe process, hydroxymethyl X can be reduced reductively to methylene,for example by catalytic hydrogenation in the presence ofpalladium-on-carbon.

Furthermore, in a compound of formula II obtainable in accordance withthe process, a carboxy group in free or reactive form may be esterifiedor amidated or an esterified or amidated carboxy group may be convertedinto a free carboxy group.

For the esterification or amidation of a carboxy group in a compound offormula II, if desired the free acid can be used or the free acid can beconverted into one of the above-mentioned reactive derivatives andreacted with an alcohol, with ammonia, or with a primary or secondaryamine, or in the case of esterification, the free acid or a reactivesalt, for example the caesium salt, can be reacted with a reactivederivative of an alcohol. For example the caesium salt of a carboxylicacid can be reacted with a halide or sulfonic acid ester correspondingto the alcohol. The esterification of the carboxy group can also becarried out using other customary alkylating agents, for example withdiazomethane, Meerwein salts or 1-substituted 3-aryltriazenes.

For the conversion of an esterified or amidated carboxy group into thefree carboxy group it is possible to use one of the methods describedabove for the removal of carboxy-protecting groups or, if desired,alkaline hydrolysis in accordance with the reaction conditions mentionedin Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften,Berlin 1988.

In compounds of formula II it is also possible to replace hydroxy R₁,R₂, R₃ and/or R₄ by one of the etherified hydroxy groups mentioned underformula II by reacting the corresponding compound of formula II whereinR₁, R₂, R₃ and/or R₄ is hydroxy in customary manner, for example in thepresence of a basic condensation agent, with a compound of theformula(e) R'₁ --Y, R'₂ --Y, R'₃ --Y and/or R'₄ --Y wherein R'₁ is loweralkyl or free or esterified or amidated carboxy-lower alkyl, R'₂ islower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-loweralkyl, cycloalkoxy-lower alkyl, optionally lower alkanoylated,halogenated or sulfonylated hydroxy-lower alkyl, oxo-lower alkyl, loweralkyl, lower alkenyl, cycloalkoxy-lower alkyl, lower alkoxy-lower alkyl,lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkyl, loweralkenyloxy-lower alkyl, lower alkenyloxy-lower alkyl, loweralkanoyl-lower alkyl, optionally S-oxidised lower alkyl-thio-loweralkyl, lower alkylthio-(hydroxy)-lower alkyl, aryl-lower alkyl,optionally hydrogenated heteroaryl-lower alkyl, optionally hydrogenatedheteroarylthio-lower alkyl, cyano-lower alkyl or free or esterified oramidated carboxy-lower alkyl, R'₃ is lower alkyl, lower alkoxy-loweralkyl, hydroxy-lower alkyl, aryl-lower alkyl, halogenated lower alkyl,cyano-lower alkyl or free or esterified or amidated carboxy-lower alkyl,and R'₄ is lower alkyl, and Y is reactive esterified hydroxy, especiallyhydroxy esterified by a mineral acid, by sulfuric acid or by an organicsulfonic acid, such as halogen, preferably chlorine, bromine or iodine,groups of the formula O--SO₂ --O--R'_(A), or lower alkanesulfonyloxy orunsubstituted or substituted benzenesulfonyloxy, especially methane-,ethane-, benzene-, p-toluene- or p-bromobenzene-sulfonyl. The reactionis, as mentioned, preferably carried out in the presence of a basiccondensation agent, such as an alkali metal carbonate, for examplepotassium carbonate, in an inert solvent, such as a lower alkanol, suchas methanol, ethanol, butanol, tert-butanol or especially amyl alcohol,advantageously at elevated temperature, for example in a temperaturerange of approximately from 40° to 140° C., if necessary with removal ofthe resulting water of reaction by distillation, for example byazeotropic distillation.

It is also possible for salts of compounds of formula II obtainable inaccordance with the process to be converted in a manner known per seinto the free compounds, for example by treatment with a base, such asan alkali metal hydroxide, a metal carbonate or metal hydrogencarbonate, or ammonia, or another of the salt-forming bases mentioned atthe beginning, or with an acid, such as a mineral acid, for example withhydrochloric acid, or another of the salt-forming acids mentioned at thebeginning.

Resulting salts can be convened into different salts in a manner knownper se: acid addition salts, for example, by treatment with a suitablemetal salt, such as a sodium, barium or silver salt, of a different acidin a suitable solvent in which an inorganic salt being formed isinsoluble and is therefore eliminated from the reaction equilibrium, andbasic salts by freeing of the free acid and conversion into a saltagain.

The compounds of formula II, including their salts, may also be obtainedin the form of hydrates or may include the solvent used forcrystallisation.

As a result of the close relationship between the novel compounds infree form and in the form of their salts, hereinabove and hereinbelowany reference to the free compounds and their salts is to be understoodas including also the corresponding salts and free compounds,respectively, as appropriate and expedient.

The invention relates also to pharmaceutical compositions comprisingcompounds of formula I.

The pharmacologically acceptable compounds of the present invention maybe used, for example, in the preparation of pharmaceutical compositionsthat comprise an effective amount of the active ingredient together orin admixture with a significant amount of inorganic or organic, solid orliquid, pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the invention arecompositions for enteral, such as nasal, rectal or oral, or parenteral,such as intramuscular or intravenous, administration to warm-bloodedanimals (human beings and animals) that comprise an effective dose ofthe pharmacological active ingredient alone or together with asignificant amount of a pharmaceutically acceptable carrier. The dose ofthe active ingredient depends on the species of warm-blooded animal,body weight, age and individual condition, individual pharmacokineticdata, the disease to be treated and the mode of administration.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, dragees, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional dissolving,lyophilising, mixing, granulating or confectioning processes.

Solutions of the active ingredient, and also suspensions, and especiallyisotonic aqueous solutions or suspensions, are preferably used, it beingpossible, for example in the case of lyophilised compositions thatcomprise the active ingredient alone or together with a carrier, forexample mannitol, for such solutions or suspensions to be made up priorto use. The pharmaceutical compositions may be sterilised and/or maycomprise excipients, for example preservatives, stabilisers, wettingagents and/or emulsifiers, solubilisers, salts for regulating theosmotic pressure and/or buffers, and are prepared in a manner known perse, for example by means of conventional dissolving or lyophilisingprocesses. The said solutions or suspensions may compriseviscosity-increasing substances, such as sodium carboxymethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as the oil component the vegetable,synthetic or semi-synthetic oils customary for injection purposes. Theremay be mentioned as such especially liquid fatty acid esters thatcontain as the acid component a long-chained fatty acid having from 8 to22, especially from 12 to 22, carbon atoms, for example lauric acid,tridecylic acid, myristic acid, pentadecylic acid, palmitic acid,margaric acid, stearic acid, arachidic acid, behenic acid orcorresponding unsaturated acids, for example oleic acid, elaidic acid,erucic acid, brassidic acid or linoleic acid, if desired with theaddition of antioxidants, for example vitamin E, β-carotene or3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fattyacid esters has a maximum of 6 carbon atoms and is a mono- orpoly-hydric, for example a mono-, di- or tri-hydric, alcohol, forexample methanol, ethanol, propanol, butanol or pentanol or the isomersthereof, but especially glycol and glycerol. The following examples offatty acid esters are therefore to be mentioned: ethyl oleate, isopropylmyristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethyleneglycerol trioleate, Gattefosse, Paris), "Miglyol 812" (triglyceride ofsaturated fatty acids with a chain length of C₈ to C₁₂, Chemische WerkeWitten/Ruhr, Germany), but especially vegetable oils, such as cottonseedoil, almond oil, olive oil, castor oil, sesame oil, soybean oil and moreespecially groundnut oil.

The injection compositions are prepared in customary manner understerile conditions; the same applies also to introducing thecompositions into ampoules or vials and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture, if desiredor necessary, after the addition of appropriate excipients, intotablets, dragee cores or capsules. They can also be incorporated intoplastics carriers that allow the active ingredients to diffuse or bereleased in measured amounts.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tri-calcium phosphate or calciumhydrogen phosphate, and also binders, such as starch pastes using, forexample, corn, wheat, rice or potato starch, gelatin, tragacanth,methylcellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired,disintegrators, such as the above-mentioned starches, alsocarboxy-methyl starch, crosslinked polyvinylpyrrolidone, agar, alginicacid or a salt thereof, such as sodium alginate. Excipients areespecially flow conditioners and lubricants, for example silicic acid,talc, stearic acid or salts thereof, such as magnesium or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable, optionally enteric, coatings, there being used, inter alia,concentrated sugar solutions which may comprise gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, orcoating solutions in suitable organic solvents, or, for the preparationof enteric coatings, solutions of suitable cellulose preparations, suchas ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Capsules are dry-filled capsules made of gelatin and also soft, sealedcapsules made of gelatin and a plasticiser, such as glycerol orsorbitol. The dry-filled capsules may comprise the active ingredient inthe form of granules, for example with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and if desired with stabilisers. In soft capsules the activeingredient is preferably dissolved or suspended in suitable oilyexcipients, such as fatty oils, paraffin oil or liquid polyethyleneglycols, it likewise being possible for stabilisers and/or antibacterialagents to be added. Dyes or pigments may be added to the tablets ordragee coatings or to the capsule casings, for example foridentification purposes or to indicate different doses of activeingredient.

The invention relates also to the use of compounds of formula I in thetreatment of disorders responsive to the inhibition of renin, such asthose mentioned at the beginning, especially hypertension and/orglaucoma.

The doses to be administered to warm-blooded animals, for example humanbeings, of, for example, approximately 70 kg body weight, especially thedoses effective in the inhibition of the enzyme renin, in lowering bloodpressure and/or in improving the symptoms of glaucoma, are fromapproximately 3 mg to approximately 3 g, preferably from approximately10 mg to approximately 1 g, for example approximately from 20 mg to 200mg, per person per day, divided preferably into 1 to 4 single doseswhich may, for example, be of the same size. Usually, children receiveabout half of the adult dose. The dose necessary for each individual canbe monitored, for example by measuring the serum concentration of theactive ingredient, and adjusted to an optimum level.

The following Examples serve to illustrate the invention; temperaturesare given in degrees Celsius, pressures in mbar.

HPLC--column dimensions: 250×4.6 mm

HPLC--column packing: Nucleosil® 5C₁₈

HPLC--eluants: A) water+0.1% by vol. trifluoroacetic acid B)acetonitrile+0. 1% by vol. trifluoroacetic acid

HPLC--gradient 0: 20-100% B in 20 minutes+8 minutes 100% B

HPLC--gradient I: linear in 60 minutes from 30% by vol. B+70% by vol. Ato 90% by vol. B +10% by vol. A

The abbreviation "R_(f) (A)" means, for example, that the R_(f) valuewas determined in solvent system A. The quantity ratio of solvents toone another is always given in parts by volume.

The same abbreviations are used for indicating the eluant systems forflash chromatography and medium pressure chromatography.

Mass-spectroscopic measurements are obtained either by conventional MSor in accordance with the "Fast-Atom-Bombardment" (FAB-MS) method. Inthe former case the mass data relate to the unprotonated molecule ion(M)⁺ or the protonated molecule ion (M+H)⁺.

The short names and abbreviations used have the following meanings:

C₁₈ -Nucleosil® brand name for reversed phase column material for HPLCcharged with octadecyl radicals (Nucleosil® 5C₁₈, Macherey & Nagel, FRG)

pFAB-MS Fast-Atom-Bombardment mass spectroscopy

FC flash chromatography

HPLC high performance liquid chromatography

Hyflo® brand name for filter aids (Fluka, Buchs, Switzerland)

IR infrared spectroscopy

b.p. at the pressure indicated in torr

ml milliliters

MS mass spectroscopy

R_(f) ratio of the migration of a substance to the distance of theeluant front from the starting point in TLC

R_(t) retention time of a substance in HPLC (in minutes)

m.p. melting point (temperature).

EXAMPLE 12(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butylphenyl)-octanoicacid (N-butyl)amide hydrochloride

111 mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide are dissolved in 2 ml of 4N hydrochloric acid indioxane at 0° C. and then stirred for 60 minutes at 20° C. The reactionmixture is concentrated by evaporation under reduced pressure and theresidue is purified by means of FC (50 g of silica gel,dichloromethane/methanol=9:1). The title compound is obtained in theform of a diastereoisomeric mixture: R_(f)(dichloromethane/methanol=9:1)=0.20; R_(t) (I)=36.6 and 37.5 minutes;FAB-MS (M+H)⁺ =419.

The starting materials are prepared as follows:

a)N-Tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide

150 m g ofN-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide (diastereoisomer I) are hydrogenated in the presenceof 150 mg of 10% Pd/C in 20 ml of tetrahydrofuran for 2 hours at roomtemperature and under normal pressure. The reaction mixture is filteredand concentrated by evaporation. The residue is purified by means of FC(50 g of silica gel, dichloromethane/diethyl ether=8:2). The titlecompound is obtained in the form of a diastereoisomeric mixture: R_(f)(dichloromethane/diethyl ether=8:2)=0.18.

b)N-Tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide

695 mg of methacrylic acid butylamide are dissolved in 30 ml oftetrahydrofuran and, at -75° C., 6.2 ml of 1.6M n-butyllithium in hexaneare added thereto. The reaction mixture is stirred for 30 minutes at 0°C. and then, at -75° C., 9.8 ml of 1M chlorotitanium triisopropoxide inhexane are added thereto. The mixture is stirred for a further 15minutes at -75° C. and then, at the same temperature, a solution of 924mg of2(S)-tert-butoxy-carbonyl-amino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanalin 10 ml of tetrahydrofuran is added dropwise thereto. The reactionmixture is then stirred further for 15 minutes at -75° C. and for 70minutes at 0° C. and then, in succession, 15 ml of 10% aqueous citricacid solution, water and diethyl ether are added thereto. The product isextracted repeatedly with diethyl ether. The diastereoisomeric mixtureis separated by FC (700 g of silica gel, eluant: dichloromethane/diethylether=9:1). The title compound is obtained: diastereoisomer I: R_(f)(dichloromethane/diethyl ether=9:1)=0.21; diastereoisomer II:

R_(f) (dichloromethane/diethyl ether=9:1)=0.14.

c)2(S)-Tert-butoxycarbonylamino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanal

At -75° C., 4.2 ml of 1.2M diisobutylaluminium hydride solution intoluene are slowly added dropwise to a solution of 1 g of2(S)-tert-butoxycarbonylamino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanoicacid methyl ester in 20 ml of toluene. The reaction mixture is thenstirred for a further 30 minutes at -70° C., 10 ml of methanol areadded, the mixture is poured onto a mixture of ice and 10 ml of 1Nhydrochloric acid, and extraction is carried out with ethyl acetate. Thetitle compound is obtained: R_(f) (dichloromethane)=0.35.

d)2(S)-Tert-butoxycarbonylamino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanoicacid methyl ester

To a solution of 2.6 g of2(S)-amino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanoic acid methylester in 50 ml of dichloromethane there are added dropwise at 0° C. 2 mlof ethyldiisopropylamine and then a solution of 2.4 g of di-tert-butyldicarbonate in 10 ml of dichloromethane. The reaction mixture is stirredfor 16 hours at room temperature and then concentrated by evaporation.The title compound is obtained by FC (240 g of silica gel, eluant:dichloromethane): R_(f) (dichloromethane)=0.50.

e) 2(S)-Amino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanoic acidmethyl ester

With stirring at room temperature, 36 ml of 1N hydrochloric acid amadded to a solution of 3.55 g of2(R)-isopropyl-5(S)-[2(S)-isopropyl-3-(p-tert-butylphenyl)-propyl]-2,5-dihydro-3,6-dimethoxy-pyrazinein 35 ml of acetonitrile and the mixture is then stirred for a further 3hours. The reaction solution is then poured onto a mixture of 45 ml ofsaturated NaHCO₃ solution and ice and the suspension is extracted withdichloromethane. The extracts arc concentrated by evaporation andpurified by FC (700 g of silica gel, eluant:dichloromethane/methanol/NH₃ =200:10:1), yielding the title compound:R_(f) (dichloromethane/methanol/conc. ammonia=200:10:1)=0.70.

f)2(R)-Isopropyl-5(S)-[2(S)-isopropyl-3-(p-tert-butyl-phenyl)-propyl]-2,5-dihydro-3,6-dimethoxypyrazine

To a solution of 2.6 ml of2(R)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine in 30 ml oftetrahydrofuran there are added dropwise, with stirring at -70° C., 8.2ml of 1.6M butyl-lithium solution in hexane and, after a further 15minutes' stirring, a solution of 2.8 g of1-bromo-2(R)-isopropyl-3-(p-tert-butyl-phenyl)-propane in 10 ml oftetrahydrofuran. The reaction mixture is stirred further for 2 hours at-70° C. and for 3 hours at -25° C., is left to stand for 20 hours at-10° C. and is then concentrated by evaporation. Saturated ammoniumchloride solution and water are added to the residue and extraction iscarried out with diethyl ether. The extracts are concentrated byevarporation and purified by FC (200 g of silica gel, eluant:dichloromethyan/hexane=1:1). The title comound is obtained: R_(f)(dichloromethane/hexane=1:1)=0.30.

g) 1-Bromo-2(R)-isopropyl-3-(p-tert-butyl-phenyl)-propane

To a solution of 2.3 g of2(R)-isopropyl-3-(p-tert-butyl-phenyl)-propanol in 50 ml ofdichloromethane there are added, with stirring at 0° C., 3.15 g oftriphenylphosphine and then, in portions, 2.14 g of N-bromosuccinimide.The reaction mixture is subsequently stirred for 16 hours at roomtemperature and is then concentrated by evaporation. The residue ispurified by FC (100 g of silica gel, eluant;dichloromethane/hexane=1:1). The title compound is obtained: R_(f)(hexane)=0.49.

h) 2(R)-Isopropyl-3-(p-tert-butyl-phenyl)-propanol

With stirring at 0° C., a solution of 8.63 g of3-[2(R)-isopropyl-3-(p-tert-butyl-phenyl)-propanoyl]-4(R)-benzyl-oxazolidin-2-onein 40 ml of tetrahydrofuran is added dropwise to a suspension of 2.41 gof LiAlH₄ in 160 ml of tetrahydrofuran. The reaction mixture is stirredfor a further 4 hours at 0° C. and then, at 0° C., 5 ml of ethylacetate, 30 ml of a mixture of tetrahydrofuran/water=1:1 and then 80 mlof 2N sulfuric acid are added in succession thereto. The suspension isextracted with ethyl acetate and the extracts are concentrated byevaporation and purified by FC (700 g of silica gel, eluant:dichloromethane). The title compound is obtained: R_(f)(dichloromethane)=0.34; m.p.=49°-51° C.

i)3-[2(R)-Isopropyl-3-(p-tert-butyl-phenyl)-propionyl]-4-(R)-benzyl-oxazolidin-2-one

30 ml of tetrahydrofuran are added to a solution of 31 ml of 1M lithiumhexamethyl-disilazide and the mixture is stirred at -70° C. A solutionof 3-isovaleroyl-4(R)-benzyloxazolidin-2-one in 20 ml of tetrahydrofuranis then added dropwise thereto and the reaction mixture is stirred for afurther 1 hour at -70° C. A solution of 9.6 g of p-tert-butyl-benzylbromide in 20 ml of tetrahydrofuran is then added dropwise thereto andthe reaction mixture is stirred for a further 1 hour at -25° C. and thenfor 4 hours at 0° C. 6 ml of saturated ammonium chloride solution arethen added to the reaction mixture, which is freed of tetrahydrofuran bymeans of concentration and then subjected to extraction with diethylether. The extract is concentrated by evaporation and the residue ispurified by FC (700 g of silica gel, eluant:dichloromethane/hexane=1:1), yielding the title compound:

R_(f) (dichloromethane/hexane=1:1)=0.30; m.p.=123.5°-124° C.

EXAMPLE 22(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-ethyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting fromN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-ethyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and is purified by FC (20 g of silica gel, eluant:dichloromethane/methanol=95:5). Title compound: R_(f)(dichloromethane/methanol=95:5)=0.09; R_(t) (I)=43.31 minutes; FAB-MS(M+H)⁺ =405.

The starting material is prepared analogously to Example 1, except thatin step i) instead of 3-isovaleroyl-4(R)-benzyl-oxazolidin-2-one thereis used 3-butyroyl-4(R)-benzyl-oxazolidin-2-one.

EXAMPLE 32(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-methyl-8-biphenyl-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from100 mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-methyl-8-biphenyl-octanoicacid (N-butyl)amide and is purified by FC (50 g of silica gel, eluant:dichloromethane/methanol=9:1). This yields the pure title compound:R_(f) (dichloromethane/methanol=9:1)=0.11; R_(t) (I)=29 minutes; FAB-MS(M+H)⁺ =411.

The starting material is obtained analogously to Example 1, except thatin step i) instead of 3-isovaleroyl-4(R)-benzyl-oxazolidin-2-one thereis used 3-propionyl-4(R)-benzyl-oxazolidin-2-one and instead ofp-tert-butyl-benzyl bromide there is used p-phenylbenzyl bromide.

EXAMPLE 42(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-ethyl-8-(4-propyloxymethyl-naphth-2-yl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from51 mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-ethyl-8-(4-propyloxy-methyl-naphth-2-yl)-octanoicacid (N-butyl)amide and is purified by means of FC (15 g of silica gel,eluant: dichloromethane/methanol=8:2). Title compound: R_(f)(dichloromethane/methanol=8:2)=0.48; FAB-MS (M+H)⁺ =471.

The starting material is obtained analogously to Example 1, step i)being altered as follows:

3-[2(S)-Ethyl-3-(4-propyloxymethyl-naphth-2-yl)-propionyl]-4(R)-benzyl-oxazolidin-2-one:

30 ml of tetrahydrofuran and a solution of 2.97 g of3-butyroyl-4(R)-benzyl-oxazolidin-2-one in 15 ml of tetrahydrofuran areadded dropwise in succession to a solution, stirred at -75° C., of 12 mlof 1M lithium hexamethyldisilazide solution. The reaction mixture isstirred for 1 hour at -75° C., a solution of 3.52 g of4-propoxymethyl-2-bromomethyl-naphthalene in 15 ml of tetrahydrofuran isadded dropwise thereto and the mixture is then stirred further for 1hour at -30° C. and for 3 hours at 0° C. After the dropwise addition at0° C. of 2.7 ml of saturated ammonium chloride solution, the reactionmixture is concentrated by evaporation and the residue is partitionedbetween diethyl ether and water. The organic extracts are concentratedby evaporation and the residue is purified by FC (1 kg of silica gel,eluant: dichloromethane/hexane=3:1), yielding the title compound: R_(f)(dichloromethane/hexane=3:1)=0.24; FAB-MS (M+Na)⁺ =482.

EXAMPLE 52(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

30 mg ofN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide are treated with 0.6 ml of 4N hydrochloric acid indioxane analogously to Example 1 and the product is purified by means ofFC (15 g of silica gel, dichloromethane/methanol=9:1). The titlecompound is obtained: R_(f) (dichloromethane/methanol=9:1)=0.17; R_(t)(I)=28.54 minutes; FAB-MS (M+H)⁺ =435.

The starting materials are prepared as follows:

a)N-Tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide

860 mg ofN-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide are hydrogenated for 3 hours at room temperature andunder normal pressure in the presence of 860 mg of 50% Pd/C in 30 ml ofmethanol. The reaction mixture is filtered and concentrated byevaporation. The residue is purified by means of FC (100 g of silicagel, dichloromethane/ethyl acetate=9:1) with separation of thediastereoisomers. The title compound is obtained: R_(f)(dichloromethane/ethyl acetate=8:2)=0.23.

The unseparated diastereoisomeric mixtureN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide has an R_(f) (ethyl acetate/hexane=1:1) of 0.38.

a')N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide can also be prepared as follows:

175 mg ofN-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide are hydrogenated in the presence of 12 mg of [Ru₂Cl₄ (S-Binap)₂ ].(NEt₃) in 30 ml of methanol for 20 hours at roomtemperature and under 30 bar. The reaction mixture is filtered,concentrated by evaporation and purified by means of FC (hexane/ethylacetate=1:1). The title compound so obtained (R_(f) in hexane/ethylacetate=1:1)=0.15 is deprotected by hydrogenation with 90 mg of 10% Pd/Cin 10 ml of methanol at room temperature and under normal pressure toformN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide.

The starting material is prepared analogously to Example 1, steps b) tog), the 2(S)-isopropyl-3-(3-benzyloxy-4-tert-butyl-phenyl)-propanol usedin step g) being prepared as follows:

h) 2(R)-Isopropyl-3-(3-benzyloxy-4-tert-butyl-phenyl)-propanol

At room temperature with stirring, to a solution of 5.65 g of2(R)-isopropyl-3-(3-hydroxy-4-tert-butyl-phenyl)-propanol in 100 ml ofdimethylformamide there are added 11 g of caesium carbonate and,dropwise, a solution of 3.2 ml of benzyl bromide in 20 ml ofdimethylformamide. The reaction mixture is stirred at room temperaturefor a further 16 hours and then concentrated by evaporation, and theresidue is partitioned between diethyl ether and water. The organicphases are concentrated by evaporation and the residue is purified by FC(90 g of silica gel, dichloromethane/hexane=9:1), yielding the titlecompound: R_(f) (dichloromethane/hexane=9:1)=0.44.

i) 2(R)-Isopropyl-3-(3-hydroxy-4-tert-butyl-phenyl)-propanol

To a solution, stirred at 0° C., of 12.3 ml of benzyl mercaptan in 100ml of tetrahydrofuran there are added dropwise 49 ml of a 1.6M solutionof butyllithium in hexane and after a further 15 minutes' stirring at 0°C. a solution of 12.1 g of3-[2(R)-isopropyl-3-(3-acetoxy-4-tert-butyl-phenyl)-propanoyl]-4(R)-benzyl-oxazolidin-2-onein 100 ml of tetrahydrofuran. The reaction solution is stirred at 0° C.for a further 90 minutes and is then added dropwise at 0° C., withstirring, to a suspension of 4.9 g of LiAlH₄ in 100 ml oftetrahydrofuran. The reaction mixture is stirred for a further 150minutes at 0° C. and then, in succession, 26.8 ml of ethyl acetate, 100ml of tetrahydrofuran/water=1:1 and 400 ml of 2N H₂ SO₄ are addeddropwise thereto. The tetrahydrofuran is removed using a rotaryevaporator and the suspension that remains is partitioned betweendiethyl ether and water. The organic phases are concentrated byevaporation and the residue is purified by FC (300 g of silica gel,dichloromethane/ethyl acetate=9:1 and 200 g of silica gel, ethylacetate/hexane=1:2), yielding the title compound: R_(f) (ethylacetate/hexane=1:2)=0.43.

k)3-[2(R)-Isopropyl-3-(3-acetoxy-4-tert-butyl-phenyl)-propanoyl]-4(R)-benzyl-oxazolidin-2-one

Analogously to Example 1e), the title compound is obtained starting from3-acetoxy-4-tert-butyl-benzyl bromide and by purification using FC(silica gel, dichloromethane/hexane=7:3): R_(f)(dichloromethane/hexane=8:2)=0.29.

l) 3-Acetoxy-4-tert-butyl-benzyl bromide

16.4 g of N-bromosuccinimide, 1 g of α,α'-azoisobutyronitrile and 1 g ofdibenzoyl peroxide are added in succession to a solution, stirred at 70°C., of 19 g of 3-acetoxy-4-tert-butyltoluene in 900 ml of CCl₄. Thereaction mixture is stirred under reflux for 31/2 hours under UVirradiation and is filtered, and the filtrate is concentrated byevaporation. The title compound is obtained from the residue by means ofFC (900 g of silica gel, hexane/ethyl acetate=95:5): R_(f) (hexane/ethylacetate=95:5)=0.40.

EXAMPLE 62(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from20 mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide by removal of the N-tert-butyloxy-carbonyl groupusing 4N hydrochloric acid in dioxane, and is purified by means of FC (8g of silica gel, dichloromethane/methanol=9:1). R_(f)(dichloromethane/methanol=8:2)=0.50; R_(t) (I) 28.47, 28.99 minutes;FAB-MS (M+H)⁺ =435.

The starting materials are prepared as follows:

a)N-Tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide

The title compound is prepared analogously to Example 5a) starting fromN-tert-butoxy-carbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-benzyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and is purified by means of FC (silica gel,hexane/ethyl acetate=2:1, ethyl acetate): R_(f) (hexane/ethylacetate=1:1)=0.36.

That starting material is obtained analogously to Example 5, the2-benzyloxy-4-tert-butyl-benzyl bromide to be used in step k) beingprepared as follows:

l) 2-Benzyloxy-4-tert-butyl-benzyl bromide

2.9 ml of trimethylsilyl bromide are added to a solution, stirred atroom temperature, of 4 g of 2-benzyloxy-4-tert-butyl-benzyl alcohol in100 ml of chloroform. The reaction mixture is stirred for a further 1hour and then partitioned between trichloromethane and water. Theorganic phases are dried with Na₂ SO₄ and concentrated by evaporation,yielding the title compound: R_(f) (dichloromethane/hexane=8:2)=0.95.

m) 2-Benzyloxy-4-tert-butyl-benzyl alcohol

A solution of 6.44 g of 2-benzyloxy-4-tert-butylbenzoic acid benzylester in 10 ml of tetrahydrofuran is slowly added dropwise to asuspension, stirred at room temperature, of 0.47 g of LiAlH₄ in 40 ml oftetrahydrofuran. The reaction mixture is stirred for a further 4 hoursat room temperature and then, in succession, 0.96 ml of ethyl acetate,6.4 ml of tetrahydrofuran/water=1:1 and 9.6 ml of 2N H₂ SO₄ are addeddropwise thereto. The suspension is partitioned between ethyl acetateand water/saturated sodium chloride solution, the organic phases areconcentrated by evaporation and the residue is purified by means of FC(150 g of silica gel, dichloromethane/hexane=6:4). Title compound: R_(f)(dichloromethane/hexane=8:2)=0.24.

n) 2-Benzyloxy-4-tert-butyl-benzoic acid benzyl ester

A mixture of 5 g of 2-hydroxy-4-tert-butyl-benzoic acid, 9.1 ml ofbenzyl bromide, 17 g of caesium carbonate, 0.3 g of sodium iodide and500 ml of acetone is stirred for 20 hours under reflux and then filteredand the filtrate is concentrated by evaporation. The residue ispartitioned between diethyl ether and water, the organic phases areconcentrated by evaporation and the residue is purified by means of FC(1000 g of silica gel, dichloromethane/hexane=1:1). Title compound:R_(f) (dichloromethane/hexane=1:1)=0.47.

EXAMPLE 72(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-ethoxycarbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from62 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-ethoxycarbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and is purified by means of FC (20 g of silica gel,dichloromethane/methanol=9:1). This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.33; R_(t) (I)=34.5 and 34.8 minutes;FAB-MS (M+H)⁺ =521.

The starting materials are obtained as follows:

a)N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-ethoxycarbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide

A mixture of 52 mg ofN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide (Example 5a), 47.5 mg of caesium carbonate, 0.012 mlof iodoacetic acid ethyl ester and 5 ml of acetone is stirred for 3hours under reflux and then concentrated by evaporation. The residue ispartitioned between diethyl ether and water. The organic phases aredried and combined and then concentrated by evaporation, yielding thetitle compound in the form of the crude product: R_(f)(dichloromethane/diethyl ether=8:2)=0.28.

EXAMPLE 82(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-allyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from45 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-allyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and is purified by FC (20 g of silica gel,dichloromethane/methanol=9:1). This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.20; FAB-MS (M+H)⁺ =475.

The starting material is prepared analogously to Example 7a) using allyliodide.

EXAMPLE 92(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxycarbonylallyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from100 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxycarbonylallyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.36;R_(t) (I)=25.32 and 25.8 minutes; FAB-MS (M+H)⁺ =533.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and 4-bromo-2-butenoic acid methyl ester.

EXAMPLE 102(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxy-carbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from91 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxy-carbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and is purified by FC (15 g of silica gel, ethylacetate/methanol=8:2). This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (ethyl acetate/methanol=8:2)=0.45;R_(t) (I)=32.5 and 33.0 minutes; FAB-MS (M+H)⁺ =507.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and bromoacetic acid methyl ester.

EXAMPLE 11 2(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-carbamoyl-methoxy-4-tert-butyl-phenyl)-octanoic acid(N-butyl)amide

Analogously to Example 1, the title compound is prepared starting from59 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-carboxamidomethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and is purified by FC (20 g of silica gel,dichloromethane/methanol/conc. ammonia=140:10:1). This yields the titlecompound in the form of a diastereoisomeric mixture: R_(f)(dichloromethane/methanol/conc. ammonia=140:10:1)=0.23 and 0.32; R_(t)(I)=25.08 and 25.59 minutes; FAB-MS (M+H)⁺ =492.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and iodoacetamide.

EXAMPLE 122(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-3-(pyrid-2-yl,methoxy)-4-tert-butyl-phenyl]-octanoic acid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from40 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-2-ylmethoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.32;R_(t) (I)=24.52 and 25.19 minutes; FAB-MS (M+H)⁺ =526.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and 2-picolyl chloride hydrochloride.

EXAMPLE 132(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-4-yl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from46 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-4-yl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.17;R_(t) (I)=20.27 and 20.62 minutes; FAB-MS (M+H)⁺ =526.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and 4-picolyl chloride hydrochloride.

EXAMPLE 142(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(N-oxido-pyrid-2-yl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from35 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(N-oxidopyrid-2-yl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol =9:1)=0.14;R_(t) (I)=31.06 and 31.6 minutes; FAB-MS (M+H)⁺ =542.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid N-(butyl)amide and 2-picolyl chloride N-oxide.

EXAMPLE 152(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxycarbonylallyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from30 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxycarbonylallyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.28;R_(t) (I)=39.3 and 39.8 minutes FAB-MS (M+H)⁺ =547.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and bromomethylacrylic acid ethyl ester.

EXAMPLE 162(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxycarbonylpropyloxy)-4-tert-butyl-phenyl-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from 9mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxycarbonyl-propyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol =9:1)=0.25;R_(t) (I)=38.5; 39.0; 39.6 and 40.2 minutes; FAB-MS (M+H)⁺ =549.

The starting material is prepared by hydrogenatingN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxycarbonylallyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide (Example 15) with Raney nickel in ethanol at roomtemperature and under 2 bar H₂ : R_(f) (ethyl acetate/hexane=1:2)=0.16.

EXAMPLE 172(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylthio-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from10 mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylthio-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.2;R_(t) (I)=29.32 and 29.56 minutes; FAB-MS (M+H)⁺ =495.

The starting material is prepared as follows:

a)N-Tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylthio-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide

A solution of 100 mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide (Example 5a) in 5 ml of dimethylformamide is addeddropwise to a suspension, stirred at room temperature, of 7.6 mg of a65% NaH dispersion in 3 ml of dimethylformamide. The reaction mixture isstirred for a further 30 minutes at room temperature and then a solutionof 0.017 ml of chlorodimethyl sulfide in 2 ml of dimethylformamide isadded thereto. The reaction mixture is stirred for a further 24 hoursand then concentrated by evaporation. The residue is partitioned betweenether and water. The organic phases are concentrated by evaporation andthe title compound is obtained from the residue by FC (12 g of silicagel, dichloromethane/diethyl ether=2:1): R_(f) (dichloromethane/diethylether=2:1)=0.33.

EXAMPLE 182(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7-(S)-isopropyl-8-[3-(methyl-sulfonyl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from15 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methyl-sulfonyl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.75;R_(t) (I)=28.3 and 28.76 minutes; FAB-MS (M+H)⁺ =527.

The starting material is prepared as follows:

a)N-Tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylsulfonyl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide

With stirring at 0° C., a solution of 115 mg of potassium monopersulfatetriple salt in 0.5 ml of water is added dropwise to a solution of 74 mgofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylthio-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide in 0.5 ml of methanol and the mixture is thenstirred at room temperature for a further 20 hours. The reaction mixtureis partitioned between dichloromethane and water. The organic phases areconcentrated by evaporation and the title compound is obtained from theresidue by FC (11 g of silica gel, ethyl acetate/hexane=1:1): R_(f)(ethyl acetate/hexane=1:1)=0.26; FAB-MS (M+H)⁺ =627.

EXAMPLE 192(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(carboxy-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from28 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(carboxy-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.26;R_(t) (I)=26.1 and 28.0 minutes; FAB-MS (M+H)⁺ =493.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-butyl-phenyl)-octanoicacid (N-butyl)amide and bromoacetic acid benzyl ester, with subsequentremoval of the benzyl group by hydrolysis (Pd/C-ethanol).

EXAMPLE 202(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3,3-dimethyl-2-oxo-butyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from42 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3,3-dimethyl-2-oxo-butyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.3;R_(t) (I)=37.3 and 37.8 minutes; FAB-MS(M+H)⁺ =533.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide and 1-bromopinacolone.

EXAMPLE 212(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-nitrobenzyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from53 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-nitrobenzyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.35;R_(t) (I)=52.0 and 52.4 minutes; FAB-MS(M+H)⁺ =570.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-butyl-phenyl)-octanoicacid (N-butyl)amide and 2-nitrobenzyl chloride.

EXAMPLE 222(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-amino-benzyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

The title compound is prepared starting from 35 mg of2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-nitrobenzyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide (Example 21 ) by hydrogenation with Pt/C intetrahydrofuran at room temperature and under normal pressure and ispurified by FC (10 g of silica gel, dichloromethane/methanol=9:1). Thisyields the title compound in the form of a diastereoisomeric mixture:R_(f) (dichloromethane/methanol=9:1)=0.27; R_(t) (I)=30.5 and 31.3minutes; FAB-MS(M+H)⁺ =539.

EXAMPLE 232(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-chloro-2(R,S)-hydroxy-propyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from31 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2,3-epoxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.18;R_(t) (I)=31.9 and 32.3 minutes; FAB-MS(M+H)⁺ =527.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butylphenyl)-octanoicacid (N-butyl)amide and epibromohydrin.

EXAMPLE 242(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylthio-2(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from15 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylthio-2(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.32;R_(t) (I)=32.6 and 32.9 minutes; FAB-MS(M+H)⁺ =53

The starting material is prepared as follows:

a)N-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylthio-2(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide

18 mg of sodium methanethiolate are added to a solution of 150 mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2,3-epoxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide in 10 ml of methanol and the mixture is maintainedunder reflux for 7 hours. The reaction mixture is concentrated byevaporation and the residue is partitioned between dichloromethane andwater. The organic phases are concentrated by evaporation and the titlecompound is obtained from the residue after purification by means of FC(20 g of silica gel, dichloromethane/diethyl ether=1:1): R_(f)(dichloromethane/diethyl ether=1:1)=0.33; FAB-MS (M+H)⁺ =639.

EXAMPLE 252(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylsulfonyl-2(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from14 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methyl-sulfonyl-2(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.16;R_(t) (I)=26.3 and 26.8 minutes; FAB-MS(M+H)⁺ =571.

The starting material is prepared analogously to Example 18a) using 62mg ofN-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylthio-2(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide: R_(f) (ethyl acetate)=0.60; FAB-MS (M+H)⁺ =671.

EXAMPLE 262(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylsulfonyl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-3-morpholino-propyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from18 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methylsulfonyl-methoxy)-4-tert-butyl-phenyl)-octanoicacid (N-3-morpholino-propyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=8:2)=0.16; R_(t) (I)=17.61 minutes;FAB-MS(M+H)⁺ =598.

The starting material is prepared analogously to Examples 17a) and 18a)usingN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)octanoicacid (N-3-morpholino-propyl)amide and chlorodimethyl sulfide.

TheN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-3-morpholino-propyl)amide is prepared analogously to Example5a-1), except that in step 5b) or 1b) methacrylic acid(N-3-morpholino-propyl)amide is used instead of methacrylic acidbutylamide.

EXAMPLE 272(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxycarbonylmethoxy-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from12 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxycarbonyl-methoxy-phenyl)-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.18; R_(t) (I)=21.74 minutes;FAB-MS(M+H)⁺ =451.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxyphenyl)-octanoicacid (N-butyl)amide and bromoacetic acid methyl ester.

TheN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxyphenyl)-octanoicacid (N-butyl)amide used as starting material is prepared analogously toExample 5a)-5l), except that in step k) instead of3-acetoxy-4-tert-butyl-benzyl bromide there is used 3-benzyloxy-benzylbromide, so that in step i)2(R)-isopropyl-3-(3-benzyloxy-phenyl)-propanol, R_(f)(dichloromethane/hexane=1:1)=0.19, is obtained directly.

EXAMPLE 282(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methoxycarbonylmethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from15 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methoxy-carbonylmethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.16; R_(t) (I)=19.33 minutes;FAB-MS(M+H)⁺ =481.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and bromoacetic acid methyl ester.

TheN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide used as starting material is prepared as follows:

a1)N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide

3.5 g ofN-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide are hydrogenated in 30 ml of absolute methanol inthe presence of 20 mg of [Ru₂ Cl₄ ((S)-Binap)₂ ].NEt₃ at roomtemperature and 25 bar for 5 hours. The reaction mixture is filtered andthe filtrate is concentrated by evaporation. The residue is purified byFC (200 g of silica gel, hexane/ethyl acetate=1:1). Title compound:R_(f) (hexane/ethyl acetate=1:1)=0.16; FAB-MS (M+H)⁺ =599.

a2)N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide

4.7 g ofN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide are hydrogenated in 60 ml of methanol in thepresence of 2.35 g of 10% Pd/C at room temperature and under normalpressure for 1 hour. Filtration of the reaction mixture andconcentration of the filtrate by evaporation under a high vacuum yieldthe title compound: R_(f) (hexane/ethyl acetate =1:1)=0.15; FAB-MS(M+H)⁺ =509.

TheN-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide used as starting material is prepared analogously toExample 1 b) to i), except that in step i) 3-benzyloxy-4-methoxy-benzylbromide is used instead of p-tert-butyl benzyl bromide.

EXAMPLE 292(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(N-methylcarbamoylmethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from18 mg ofN-tert-butoxy-carbonyl-2(R)-methoxy-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(N-methyl-carbamoylmethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.21; R_(t) (I)=15.54 minutes;FAB-MS(M+H)⁺ =480.

The starting material is prepared as follows:

A mixture of 29 mg ofN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methoxycarbonylmethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide (Example 32), 6 ml of dimethylformamide and 1 ml ofmethylamine is left to stand in a bomb tube at room temperature for 60hours. Concentration by evaporation and FC (5 g of silica gel,dichloromethane/methanol=9:1) of the residue yield the title compound:R_(f) (dichloromethane/methanol=9:1)=0.55.

EXAMPLE 302(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methyl-sulfonyl-propyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from30 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylsulfonyl-propyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.29; R_(t) (I)=17.83 minutes;FAB-MS(M+H)⁺ =529.

The starting material is prepared analogously to Examples 17a) and 18a)usingN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-methoxy-phenyl)-octanoicacid (N-butyl)amide and 3-methylthiopropyl iodide with subsequentoxidation to the sulfone.

EXAMPLE 312(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylsulfonyl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from100 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylsulfonyl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=8:2)=0.5; R_(t) (I)=18.0 minutes; FAB-MS(M+H)⁺=501.

The starting material is prepared analogously to Examples 17a) and 18a)usingN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and chlorodimethyl sulfide with subsequent oxidationto the sulfone.

EXAMPLE 322(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methoxy-propyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from27 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methoxy-propyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide and is purified by FC (2 g of silica gel,dichloromethane/methanol=95:5). This yields the title compound: R_(f)(dichloromethane-methanol=9:1)=0.15; R_(t) (I)=21.9 minutes;FAB-MS(M+H)⁺ =481.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 3-methoxy-propyl iodide.

EXAMPLE 332(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-methoxyethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from68 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-methoxyethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.32; R_(t) (I)=19.84 minutes;FAB-MS(M+H)⁺ =467.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 2-methoxy-ethyl iodide.

EXAMPLE 342(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-hydroxy-propyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from93 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-hydroxy-propyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9: 1)=0.24; R_(t) (I)=16.13 minutes;FAB-MS(M+H)⁺ =467.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 3-iodopropanol.

EXAMPLE 352(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(carbamoyl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from39 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(carbamoyl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=8:2)=0.38; R_(t) (I)=13.86 minutes;FAB-MS(M+H)⁺ =466.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and iodoacetamide.

EXAMPLE 362(R)-Methyl-4(S)-hydroxy-5-(S)-amino-7(S)-isopropyl-8-(3-cyanomethoxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide

1.5 ml of a mixture of trifluoroacetic acid/dichloromethane=1:3 areadded at 0° C., with stirring, to a solution of 35 mg ofN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-cyanomethoxy-4-methoxy-phenyl)-octanoicacid (N-butyl)-amide in 1 ml of dichloromethane, and the mixture isstirred for a further 3 hours at 0° C. and then concentrated byevaporation. The residue is purified by FC (5 g of silica gel,dichloromethane/methanol=9:1). This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.19; R_(t) (I)=19.59 minutes;FAB-MS(M+H)⁺ =448.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and iodoacetonitrile.

EXAMPLE 372(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(4-methoxybutoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from24 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(4-methoxy-butoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.29; R_(t) (I)=22.51 minutes;FAB-MS(M+H)⁺ =495.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 4-methoxy-propyl iodide.

EXAMPLE 382(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxy-ethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from24 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxy-ethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.26; R_(t) (I)=21.32 minutes;FAB-MS(M+H)⁺ =481.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 2-iododiethyl ether.

EXAMPLE 392(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-{3-[2-(2-methoxy-ethoxy)ethoxy]-4-methoxy-phenyl}-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from27 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-{3-[2-(2-methoxy-ethoxy)ethoxy]-4-methoxy-phenyl}-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=1:1)=0.19; R_(t) (I)=18.93 minutes;FAB-MS(M+H)⁺ =511.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 1-iodo-2-(2-methoxy-ethoxy)-ethane.

EXAMPLE 402(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-pentyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from53 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-pentyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.25; R_(t) (I)=32.01 minutes;FAB-MS(M+H)⁺ =479.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and iodopentane.

EXAMPLE 412(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from100 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.31; R_(t) (I)=44.21 minutes;FAB-MS(M+H)⁺ =499.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and benzyl bromide.

EXAMPLE 422(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-ethoxy-propyloxy)-4-methoxy-phenyl-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from113 mg ofN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-ethoxypropyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.30; R_(t) (I)=23.11 minutes;FAB-MS(M+H)⁺ =495.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 1-ethoxy-3-iodopropane.

EXAMPLE 432(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-4-yl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from71 mg ofN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-4-yl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.19; R_(t) (I)=32.95 minutes; FAB-MS(M+H)⁺ =500.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide and 4-picolyl chloride.

EXAMPLE 442(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-ethoxy-carbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from67 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-ethoxy-carbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)-amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.19;R_(t) (I)=35.7 and 36.5 minutes; FAB-MS(M+H)⁺ =521.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide (Example 6a) and iodoacetic acid ethyl ester.

EXAMPLE 452(R,S)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-ethoxy-carbonyl-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from80 mg ofN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-ethoxy-carbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide. This yields the title compound in the form of adiastereoisomeric mixture: R_(f) (dichloromethane/methanol=9:1)=0.21;R_(t) (I)=27.8 and 28.39 minutes; FAB-MS(M+H)⁺ =492.

The starting material is prepared analogously to Example 7a) usingN-tert-butoxy-carbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide (Example 6a) and iodoacetamide.

EXAMPLE 462(R)-Methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methoxy-propyloxy)-4,5-ethylenedioxy-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from34 mg ofN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methoxy-propyloxy)-4,5-ethylenedioxy-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.16; R_(f) (I)=21.83 minutes; FAB-MS(M+H)⁺ =509.

The starting material is prepared analogously to Example 17a) usingN-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4,5-ethylenedioxy-phenyl)-octanoicacid (N-butyl)amide and 3-methoxy-propyl iodide.

TheN-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4,5-ethylenedioxy-phenyl)-octanoicacid (N-butyl)amide is prepared analogously to Example 28, except thatin step i) instead of 3-benzyloxy-4-methoxy-benzyl bromide there is used3-benzyloxy-4,5-ethylenedioxy-benzyl bromide. That compound is preparedas follows:

a) 5-Hydroxy-1,4-benzodioxane-7-carboxylic acid ethyl ester

A solution of 0.2 ml of 1,2-dibromoethane in 4 ml of dimethylformamideis added dropwise, four times at 2 hour intervals, to a solution,stirred at 100° C., of 2 g of gallic acid ethyl ester and 6.5 g ofcaesium carbonate in 80 ml of dimethylformamide. After being stirred fora further 2 hours at 100° C. the reaction mixture is concentrated byevaporation and the residue is partitioned between diethyl ether andwater. The organic phases are dried over sodium sulfate and concentratedby evaporation. The title compound is obtained from the residue by FC(50 g of silica gel, methylene chloride-methanol=8:2): R_(f) (methylenechloride/methanol=8:2)=0.39.

b) 5-Benzyloxy-1,4-benzodioxane-7-carboxylic acid ethyl ester

The reaction mixture containing 900 ml of acetone, 17.4 g ofhydroxy-1,4-benzodioxane-7-carboxylic acid ethyl ester, 37.9 g ofcaesium carbonate, 11 ml of benzyl bromide and 7.7 g of sodium iodide isstirred under reflux for 3 hours and then concentrated by evaporation.The residue is partitioned between diethyl ether and water. The organicphases are dried over sodium sulfate and concentrated by evaporation.The title compound is obtained from the residue by FC (900 g of silicagel, hexane/ethyl acetate=1:1): R_(f) (hexane/ethyl acetate=2:1)=0.36.

c) 5-Benzyloxy-7-hydroxymethyl-1,4-benzodioxane

A solution of 1.28 g of 5-benzyloxy-1,4-benzodioxane-7-carboxylic acidethyl ester in 5 ml of tetrahydrofuran is added dropwise at roomtemperature to a solution of 110 mg of lithium aluminium hydride in 10ml of tetrahydrofuran and the mixture is stirred at room temperature fora further 30 minutes. Then 0.22 ml of ethyl acetate, 1.5 ml of a mixture(water/tetrahydrofuran=1:1) and finally 2.25 ml of 2N sulfuric acid areadded dropwise in succession. The reaction mixture is partitionedbetween diethyl ether and water. The organic phases are dried oversodium sulfate and concentrated by evaporation. The title compound isobtained from the residue by FC (240 g of silica gel, ethylacetate/hexane=1:2): R_(f) (ethyl acetate-hexane=1:2)=0.18.

d) 3-Benzyloxy-4,5-ethylenedioxy-benzyl bromide

0.07 ml of trimethylsilyl bromide is added to a solution of 0.1 g of5-benzyloxy-7-hydroxymethyl-1,4-benzodioxane in 5 ml of chloroform andthe mixture is stirred for a further 15 minutes at room temperature andthen concentrated by evaporation in a rotary evaporator. The residue isimmediately dissolved in a small amount of ethyl acetate; the samevolume of hexane is added and the mixture is filtered through 15 g ofsilica gel, followed by elution with a mixture (hexane/ethylacetate=4:1). Concentration of the eluates by evaporation yields thetitle compound: R_(f) (hexane/ethyl acetate=3:1)=0.48.

EXAMPLE 47

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-hydroxy-propyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide hydrochloride.

EXAMPLE 48

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-isopropyl-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide hydrochloride.

EXAMPLE 49

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-tert-butyl-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]amide hydrochloride.

EXAMPLE 50

In a manner analogous to that described in Examples 1 to 46 or 62 to180, it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-methyl-sulfonyl-propyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-2-morpholinoethyl)amide dihydrochloride.

EXAMPLE 51

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-methyl-sulfonyl-propyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide hydrochloride.

EXAMPLE 52

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3,4-di(3-hydroxypropyloxy)phenyl]-octanoicacid (N-2-morpholinoethyl)amide dihydrochloride.

EXAMPLE 53

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3,4-di(3-hydroxypropyloxy)phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide hydrochloride.

EXAMPLE 54

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-N-methylcarbamoyl-propyl)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-2-morpholinoethyl)amide dihydrochloride.

EXAMPLE 55

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(2-morpholinoethoxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide dihydrochloride.

EXAMPLE 56

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxy-propyloxy)-4,5-ethylenedioxy-phenyl]-octanoicacid (N-2-morpholinoethyl)amide dihydrochloride.

EXAMPLE 57

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxy-propyloxy)-4,5-ethylenedioxy-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide hydrochloride.

EXAMPLE 58

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxy-propyloxy)-4,5-methylenedioxy-phenyl]-octanoicacid (N-2-morpholinoethyl)amide dihydrochloride.

EXAMPLE 59

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxy-propyloxy)-4,5-methylenedioxy-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethylethyl)]-amide hydrochloride.

EXAMPLE 60

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-ethylene-ethyl)]-amide hydrochloride.

EXAMPLE 61

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(S)-2-oxo-pyrrolidin-3-yl-methyl)]amide hydrochloride.

EXAMPLE 625(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(4-methoxy-but-2-enoxy)-phenyl]-octanoicacid (N-butyl)-amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from66 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(4-methoxy-but-2-enoxy)-phenyl]-octanoicacid (N-butyl)-amide and is purified by FC (30 g of silica gel,dichloromethane/methanol=9:1). This yields the title compound: Rf(dichloromethane/methanol=9:1)=0.26; HPLC R_(t) (I)=40.4 minutes; FAB-MS(M+H)⁺ =493.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-(3-hydroxy-4-methoxy-phenyl)-octanoicacid (N-butyl)-amide (Example 28) and 4-methoxy-but-2-enyl iodide.

EXAMPLE 635(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from20 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)-amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.05; HPLC R_(t) (I)=36.22 minutes;FAB-MS (M+H)⁺ =467.

The starting material is prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)-amide

1.34 g of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-benzyloxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)-amide are hydrogenated in the presence of 400 mg of 5%Pd/C in 50 ml of methanol for 10 minutes at room temperature and undernormal pressure. The reaction mixture is filtered and concentrated byevaporation. The residue is purified by means of FC (50 g of silica gel,hexane/ethyl acetate=1:1). The title compound is obtained: R_(f)(hexane/ethyl acetate=1:1)=0.16; HPLC R_(t) =17.42 minutes; FAB-MS:(M+H)⁺ =567.

The5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-benzyloxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)-amide used as starting material is prepared analogouslyto Example 28a1) and Examples 1b) to 1g), except that in step g) insteadof 2(S)-isopropyl-3-(p-tert-butyl-phenyl)-propanol there is used2(S)-isopropyl-3-[4-benzyloxy-3-(3-methoxypropyloxy)-phenyl]-propanol.That compound is prepared analogously to Example 124i) to m), exceptthat in step m) instead of 4-methoxy-3-(3-methoxypropyloxy)-benzylalcohol there is used 4-benzyloxy-3-(3-methoxypropyloxy)-benzyl alcohol.

That compound is prepared as follows:

b) 4-Benzyloxy-3-(3-methoxypropyloxy)-benzaldehyde

A solution of 28.8 g of 4-benzyloxy-3-hydroxy-benzaldehyde in 100 ml ofdimethyl-formamide is added dropwise to a suspension of 5.54 g of NaH(60% dispersion in mineral oil) in 150 ml of absolute dimethylformamide.The reaction mixture is stirred at room temperature. After 30 minutes, asolution of 29 g of 3-methoxybromopropane in 120 ml of dimethylformamideis added thereto, and the mixture is stirred at room temperature for afurther 4 hours and is then concentrated by evaporation under reducedpressure. The residue is partitioned between diethyl ether and water.The combined organic phases are dried over sodium sulfate andconcentrated by evaporation, and the residue is purified by FC (100 g ofsilica gel, dichloromethane), yielding the title compound, whichcrystallises spontaneously: R_(f) (dichloromethane/diethyl ether)=0.44.

c) 4-Benzyloxy-3-(3-methoxypropyloxy)-benzyl alcohol

A solution of 31 g of 4-benzyloxy-3-(3-methoxypropyloxy)-benzaldehyde in530 ml of ethanol/water=8:2 is added dropwise to a suspension, stirredat 0° C., of 11.74 g of sodium boranate in 530 ml of a mixture ofethanol/water=8:2. The reaction mixture is stirred for one hour at 0° C.and is then concentrated by evaporation. The residue is partitionedbetween diethyl ether and water. The combined organic phases are driedover sodium sulfate and concentrated by evaporation, and the residue ispurified by FC (100 g of silica gel, dichloromethane/diethyl ether=1:1),yielding the title compound: R_(f) (dichloromethane/diethylether=1:1)=0.43.

EXAMPLE 645(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-benzyloxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from60 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-benzyloxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=95:5)=0.08; HPLC R_(t) (I)=45.47 minutes;FAB-MS (M+H)⁺ =557.

EXAMPLE 655(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[3,4-di(3-methoxypropyloxy)phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from66 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[3,4-di(3-methoxypropyloxy)phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: Rf(dichloromethane/methanol=9:1)=0.21; R_(t) (I)=40.0 minutes; FAB-MS(M+H)⁺ =539.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and 3-methoxy-bromopropane.

EXAMPLE 665(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(2,2,2-trifluoroethoxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from14 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(2,2,2-trifluoro-ethoxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.31; HPLC R_(t) (I)=28.7 minutes; FAB-MS(M+H)⁺ =549.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxy-carbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and 2,2,2-trifluoroethyl iodide.

EXAMPLE 675(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from20 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-hydroxy-propyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide and is purified by FC (2 g of silica gel,dichloromethane/methanol=9:1). This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.09; HPLC R_(t) =11.03 minutes; FAB-MS(M+H)⁺ =525.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxy-carbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and 3-iodopropanol.

EXAMPLE 685(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-S-[4-(2-amino-ethoxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from7.5 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(2-amino-ethoxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol/conc. ammonia=100:50:1)=0.28; HPLC R_(t) =6.77minutes; FAB-MS (M+H)⁺ =510.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxy-carbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and iodoacetonitrile, with subsequent reduction ofthe nitrile function to the amino group with Raney nickel/H₂ undernormal pressure and at 40° C. in ethanol in the presence of 4% ammonia.

EXAMPLE 695(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(5-amino-pentyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from22 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(5-amino-pentyloxy)-3-(3-methoxypropyloxy)-phenyl]octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol/conc. ammonia=100:50: 1)=0.11; HPLC R_(t)=7.46 minutes; FAB-MS (M+H)⁺ =552.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and 5-iodovaleric acid nitrile, with subsequentreduction of the nitrile function to the amino group with Raneynickel/H₂ under normal pressure and at 40° C. in ethanol in the presenceof 4% ammonia.

EXAMPLE 705(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-amino-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from36 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-amino-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol/ammonia (conc.)=100:50:1)=0.15; HPLC R_(t)(I)=33.3 minutes; FAB-MS (M+H)⁺ =538.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxy-carbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and 4-iodobutyronitrile, with subsequent reductionof the nitrile function to the amino group with Raney nickel/H₂ undernormal pressure and at 40° C. in ethanol in the presence of 4% ammonia,to form5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-amino-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide, R_(f) (dichloro-methane/methanol/conc.ammonia=100:50:1)=0.15, HPLC R_(t) =13.55 minutes.

EXAMPLE 715(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-N,N-dimethylamino-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from30 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-N,N-dimethylamino-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol/ammonia (conc.)=100:50:1)=0.21; HPLC R_(t)=9.7 minutes; FAB-MS (M+H)⁺ =566.

The starting material is prepared by hydrogenation of 80 mg of5(S)-tert-butoxycarbonyl-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-amino-butyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide (Example 70), dissolved in 6 ml of methanol and inthe presence of 25 ml of 35% formaldehyde solution, with 30 mg of 10%Pd/C for a period of 19 hours at room temperature and under normalpressure, and is purified by FC (5 g of silica gel,dichloromethane/methanol/ammonia (conc.)=350:50: 1). R_(f)(dichloromethane/methanol/conc. ammonia=350:50:1)=0.21; HPLC R_(t)=14.18 minutes; FAB-MS (M+H)⁺ =666.

EXAMPLE 725(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-{4-[4-N-(trifluoromethanesulfonylaminobutyloxy)-3-(3-methoxypropyloxy),phenyl]}-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from27 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-{4-[4-N-(trifluoromethanesulfonylaminobutyloxy)-3-(3-methoxypropyloxy)-phenyl]}-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.27; HPLC R_(t) =14.67 minutes; FAB-MS(M+H)⁺ =670.

The starting material is prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-N-trifluoromethanesulfonylamido-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide

50 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-aminobutyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)-amide are dissolved in 4 ml of dichloromethane, and 23 mlof triethylamine and 13 ml of trifluoromethanesulfonic acid anhydrideare added thereto at 0° C. The reaction mixture is stirred for 2 hoursat room temperature and is then partitioned between dichloromethane (3x)and saturated NaHCO₃ solution (1x). The organic phases are combined,dried over magnesium sulfate and concentrated by evaporation.Purification of the residue by FC (15 g of silica gel, hexane/ethylacetate=1:1) yields the title compound: R_(f) (hexane/ethylacetate=1:1)=0.26; HPLC R_(t) =20.02 minutes.

EXAMPLE 735(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-carboxy-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from70 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-carboxy-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=7:3)=0.35; HPLC R_(t) (I)=37.18 minutes;FAB-MS (M+H)⁺ =525.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxy-carbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and bromoacetic acid benzyl ester, with subsequentdebenzylation in ethanol with 10% Pd/C at room temperature and undernormal pressure.

EXAMPLE 745(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-ethoxycarbonyl-propyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)-amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from27 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-ethoxy-carbonylpropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.24; HPLC R_(t) =18.18 minutes; FAB-MS(M+H)⁺ =581.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxy-carbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and 4-iodobutyric acid ethyl ester.

EXAMPLE 755(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-carboxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from41 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-carboxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.20; HPLC R_(t) (I)=37.65 minutes;FAB-MS (M+H)⁺ =553.

The starting material is prepared from5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-ethoxycarbonylpropyloxy)-3-(3-methoxypropyloxy)phenyl]-octanoicacid (N-butyl)amide (Example 74) by hydrolysis of the ester function inmethanolic solution with 2 equivalents of 1N sodium hydroxide, bystirring for 24 hours at room temperature. The reaction mixture isconcentrated by evaporation, an aqueous solution of the residueacidified to pH 4 is extracted with ethyl acetate, and the productobtained therefrom is purified by FC (dichloromethane/methanol=9:1).R_(f) (dichloromethane/methanol=95:5)=0.41.

EXAMPLE 765(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-methoxy-carbonylbutyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from29 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-methoxy-carbonyl-butyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.24; HPLC R_(t) (I)=42.55 minutes;FAB-MS (M+H)⁺ =581.

The starting material is prepared analogously to Example 17a) using5(S)-tert-butoxy-carbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide and 5-iodovaleric acid methyl ester.

EXAMPLE 775(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-carboxy-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from10 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-carboxy-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=8:2)=0.34; HPLC R_(t) =9.92 minutes; FAB-MS(M+H)⁺ =567.

The starting material is prepared from5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-methoxycarbonyl-butyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide (Example 76) by hydrolysis of the ester function inmethanolic solution with 2 equivalents of 1N sodium hydroxide, bystirring for 24 hours at room temperature. The reaction mixture isconcentrated by evaporation, the residue is dissolved in water, and thesolution is acidified to pH 4 and extracted with ethyl acetate. Theorganic phases are dried over magnesium sulfate and concentrated byevaporation. Purification of the residue by FC (silica gel,dichloromethane/methanol=9:1) yields the title compound: R_(f)(dichloromethane/methanol/conc. ammonia=350:50:1)=0.14.

EXAMPLE 78

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(R)-2-oxo-pyrrolidin-3-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(S)-2-oxo-piperidin-3-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(R)-2-oxo-piperidin-3-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-carbamoyl-3,3-dimethyl-propyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-butyl)-phenyl]-octanoicacid [N-(5(S)-2-pyrrolidinon-5-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-butyl)-phenyl]-octanoicacid [N-(5(R)-2-pyrrolidinon-5-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(6(S)-2-oxo-piperidin-6-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(6(R)-2-oxo-piperidin-6-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-thiazol-2-yl-ethyl)]-amide dihydrochloride,

5(S)-amino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4(S)-2-oxazolidinon-4-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4(R)-2-oxazolidinon-4-yl-methyl) ]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(S)-2,5-dioxo-pyrrolidin-3-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(R)-2,5-dioxo-pyrrolidin-3-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2,6-dioxo-piperidin-4-yl-methyl)]-amide hydrochloride, or

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4(S)-2-oxothiazolidin-4-yl-methyl)]-amide hydrochloride.

EXAMPLE 79

In a manner analogous to that described in Examples 1 to 46 or 62 to 180it is also possible to prepare

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxypropoxy)-4,5-ethylene-dioxy-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)phenyl]-octanoicacid [N-(4(R)-2-oxothiazolidin-4-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(tetrahydro-2-pyrimidon-5-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(N-acetyl-2-amino-2-methyl-propyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(N-formyl-2-amino-2-methyl-propyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4-acetyl-piperazinyl-ethyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2,4-imidazolinedion-5-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-butyl)-phenyl]-octanoicacid [N-(2-hydroxy-pyridin-6-yl-methyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2,2-dimethyl-2-sulfamoyl-ethyl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2,2-dimethyl-2-(N,N-dimethyl)-sulfamoyl-ethyl)]-amidehydrochloride,

5(S)-amino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-oxo-piperidin-3(R)-yl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-oxo-piperidin-3(S)-yl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-oxo-piperidin-4-yl)]-amide hydrochloride,

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(N-acetyl-piperidin-4-yl)]-amide hydrochloride, or

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-but-1-enyl)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide hydrochloride.

EXAMPLE 805(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide hydrochloride

Analogously to Example 1, the title compound is prepared starting from82 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-(4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide. This yields the title compound: R_(f)(dichloromethane/methanol=9:1)=0.32; HPLC R_(t) (I)=42.32 minutes;FAB-MS (M+H)⁺ =509.

The starting material is prepared analogously to Examples 206a) and200b) from3-tert-butoxycarbonyl-5(S)-[2(S)-carboxy-3-methyl-butyl]-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 200 c) and n-butylamine.

EXAMPLE 815(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-octanoicacid (N-butyl)amide

50 mg of5(S)-azido-4(S)-hydroxy-8(R,S)-isobutyroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-octanoicacid (N-butyl)amide are hydrogenated in 10 ml of methanol in thepresence of 50 mg of 10% Pd/C at room temperature and under normalpressure. The reaction mixture is filtered and concentrated byevaporation. The residue is purified by means of FC (2 g of silica gel,dichloromethane/methanol=9:1). The title compound is obtained: R_(f)(dichloromethane/methanol=9:1)=0.19; HPLC R_(t) =13.42 minutes; FAB-MS(M+H)⁺ =509.

The starting material is prepared as follows:

a) 2-(2-Hydroxyethyl)-anisole

To a solution of 10 g of 2-(2-hydroxyphenyl)-ethanol in 200 ml ofacetone there are added 35.3 g of Cs₂ CO₃ and then a solution of 6.5 mlof methyl iodide in 40 ml of acetone. The reaction mixture is stirredfor 50 minutes at room temperature, is filtered and is concentrated byevaporation. The residue is partitioned between diethyl ether and water.The organic phases are combined, dried over magnesium sulfate andconcentrated by evaporation, and the residue is purified by means of FC(dichloromethane/diethyl ether=97:3), yielding the title compound: R_(f)(dichloromethane/diethyl ether=97:3)=0.34; HPLC R_(t) =9.31 minutes.

b) 4-Bromo-2-(2-hydroxyethyl)-anisole

35.72 g of tetrabutylammonium tribromide am added in portions to asolution of 10.7 g of 2-(2-hydroxyethyl)-anisole in 195 ml ofdichloromethane and 130 ml of methanol. The reaction mixture is stirredfor 150 minutes at room temperature and is then concentrated byevaporation in a rotary evaporator. The residue is partitioned betweendiethyl ether and water. The organic phases are combined, dried overmagnesium sulfate and concentrated by evaporation, and the residue ispurified by means of FC (dichloromethane), yielding the title compound:R_(f) (dichloromethane)=0.26; HPLC R_(t) =13.04 minutes.

c) 4-Bromo-2-(2-methoxymethoxy-ethyl)-anisole

1.48 g of N-ethyl-diisopropylamine and 0.49 g of chlorodimethyl etherare added at room temperature to a solution of 948 mg of4-bromo-2-(2-hydroxyethyl)-anisole in 30 ml of dichloromethane. Thereaction mixture is stirred for 200 minutes at room temperature, andthen 1 ml of water and 1 ml of 25% ammonium hydroxide solution are addedthereto. The two-phase mixture is stirred vigorously for a further 15minutes and then the organic phase is separated off, dried over sodiumsulfate and concentrated by evaporation. Purification of the residue bymeans of FC (hexane/dichloromethane=1:1) yields the title compound:R_(f) (dichloromethane)=0.5; HPLC R_(t) =17.33 minutes.

d)3(S)-Isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-hydroxy-4-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-butyl}-tetrahydrofuran-2-one

Several iodine crystals am added to a suspension of 763 mg of magnesiumchips in 0.5 ml of tetrahydrofuran, and the mixture is activated in anultrasound bath for 30 minutes. Then 4 drops of 1,2-dibromoethane andthen a solution of 8.64 g of 4-bromo-2-(2-methoxymethoxyethyl)-anisolein 30 ml of tetrahydrofuran are added dropwise in such a manner that thereaction mixture boils under reflux. When the addition is complete, themixture is maintained under reflux for a further one hour. The reactionmixture is then added dropwise within a period of 45 minutes, withstirring, to a solution, cooled to -75° C., of 2.85 g of3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-onein 20 ml of tetrahydrofuran. The reaction mixture is stirred for afurther 150 minutes at -75° C., and there are then added thereto, at thesame temperature, a solution of 1.4 ml of glacial acetic acid in 1 ml oftetrahydrofuran and then 25 ml of saturated ammonium chloride solution.The reaction mixture is then brought to room temperature, poured onto 60ml of water and extracted three times with 100 ml of ethyl acetate. Theorganic phases are washed with 50 ml of saturated sodium chloridesolution, combined, dried over magnesium sulfate and concentrated byevaporation. Purification of the residue by means of FC (400 g of silicagel, hexane/ethyl acetate=8:2) yields the title compound: R_(f)(hexane/ethyl acetate=7:3)=0.25; HPLC R_(t) =48.10 and 50.29 minutes(diastereoisomeric mixture).

e)3(S)-Isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-isobutyryloxy-4-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-butyl}-tetrahydrofuran-2-one

0.25 ml of pyridine, 0.31 ml of isobutyric acid anhydride and 15 mg ofdimethylamino-pyridine are added to a solution of 300 mg of3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-hydroxy-4-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-butyl}-tetrahydrofuran-2-onein 3.5 ml of dichloromethane, and the mixture is stirred for 80 hours atroom temperature. The reaction mixture is then partitioned betweendichloromethane (3x), water (1x) and saturated sodium chloride solution(2x). The combined organic phases are dried over magnesium sulfate andconcentrated by evaporation, and the residue is purified by FC (30 g ofsilica gel, hexane/ethyl acetate=8:2), yielding the title compound:R_(f) (hexane/ethyl acetate=8:2)=0.26; HPLC R_(t) =21.38 minutes and21.76 minutes (diastereoisomeric mixture).

f)5(S)-Azido-4(S)-hydroxy-2(S),7(S)-diisopropyl-8(R,S)-isobutyryloxy-8-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-octanoicacid (N-butyl)-amide

A solution of 170 mg of3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-isobutyryloxy-4-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-butyl}-tetrahydrofuran-2-onein 1.4 ml of butylamine is stirred for 16 hours at room temperature andis then concentrated by evaporation. Purification of the residue bymeans of FC (hexane/ethyl acetate=7:3) yields the title compound: R_(f)(hexane/ethyl acetate=7:3)=0.25; HPLC R_(t) =20.38 and 20.8 minutes(diastereoisomeric mixture).

The3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxo-butyl]-tetrahydrofuran-2-oneused in step d) is prepared as follows:

g) 2(S),7(S)-Diisopropyl-oct-4-ene-dicarboxylic acid[bis([4(S)-benzyl-oxazolidin-2-one)]-amide

48 ml of a 1.0M solution of lithium hexamethyldisilazide intetrahydrofuran are added dropwise, with stirring, at -75° C., within aperiod of one hour, to a solution of 11.5 g of4(S)-benzyl-3-isovaleroyl-oxazolidin-2-one in 32 ml of tetrahydrofuran.The mixture is stirred further for 2 hours at -75° C. and for 20 minutesat -20° C., and there are then added thereto 10 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidone (DMPU) and, within aperiod of 45 minutes, a solution of 4.28 g of 1,4-dibromo-2-butene in 10ml of tetrahydrofuran. The reaction mixture is stirred for a further 15hours at -20° C. and is then brought to 0° C. within a period of onehour; 10 ml of saturated ammonium chloride solution are then addedthereto at -20° C. and, after 15 minutes, the mixture is brought to roomtemperature. The reaction mixture is then partitioned betweendichloromethane and saturated sodium chloride solution/water=1:1. Theorganic phases are combined, dried over sodium sulfate and concentratedby evaporation, and the residue is purified by means of FC (hexane/ethylacetate=4:1), yielding the title compound: R_(f) (hexane/ethylacetate=4:1)=0.30; HPLC R_(t) =21.6 minutes; FAB-MS (M+H)⁺ =575;m.p.=110°-111° C. (crystallised from ethyl acetate/hexane).

h) 3(S)-Isopropyl-5(S)-{1(R)-bromo-4-methyl-3(S)-[(4(S)-benzyloxazolidin-2-on-3-yl)-carbonyl]-pentyl}-tetrahydrofuran-2-one

10.5 g of N-bromosuccinimide are added, with stirring, to a solution of30 g of 2(S),7(S)-diisopropyl-oct-4-ene-dicarboxylic acid[bis(4(S)-benzyl-oxazolidin-2-one)]-amide in 360 ml of tetrahydrofuranand 120 ml of water, the temperature being maintained at roomtemperature with an ice-bath. The reaction mixture is stirred for afurther 2 hours at room temperature, and then the tetrahydrofuran isevaporated off in a rotary evaporator. The aqueous residue ispartitioned between diethyl ether (2×200 ml), water (2×50 ml) andsaturated sodium chloride solution (1×50 ml). The organic phases arecombined, dried over magnesium sulfate and concentrated by evaporation,and the residue is purified by means of FC (90 g of silica gel,hexane/ethyl acetate=3:1), yielding the title compound in the form of acrude product. Crystallisation from diisopropyl ether yields the purecompound: m.p.=91°-92° C.; R_(f) (hexane/ethyl acetate=8:2)=0.28; HPLCR_(t) =19.53 minutes; FAB-MS (M+H)⁺ =494.

i)3(S)-Isopropyl-5(S)-{1(S)-azido-4-methyl-3(S)-[(4(S)-benzyl-oxazolidin-2-on-3-yl)-carbonyl]-pentyl}-tetrahydrofuran-2-one

13.6 g of freshly dried tetrabutylammonium azide are added to asolution, stirred at room temperature, of 17.8 g of3(S)-isopropyl-5(S)-{1(R)-bromo-4-methyl-3(S)-[(4(S)-benzyl-oxazolidin-2-on-3-yl)-carbonyl]-pentyl}-tetrahydrofuran-2-onein 180 ml of toluene, and a further 10 g of the azide are added in thecourse of 160 hours' stirring at room temperature. The reaction mixtureis then partitioned between ethyl acetate and water (2x) and saturatedsodium chloride solution (1x). The organic phases are combined, driedover sodium sulfate and concentrated. The title compound is obtainedfrom the evaporation residue by means of FC (hexane/ethyl acetate=8:2)and crystallisation from diethyl ether/hexane: m.p.=102°-103° C.; R_(f)(hexane/ethyl acetate=8:2)=0.2; HPLC R_(t) =18.55 minutes; FAB-MS (M+H)⁺=457.

k)3(S)-Isopropyl-5(S)-(1(S)-azido-3(S)-carboxy-4-methyl-pentyl)-tetrahydrofuran-2-one

175 ml of water, 74 ml of 30% hydrogen peroxide solution and 5.9 g oflithium hydroxide are slowly added in succession to a solution, stirredat -5° C., of 55.3 g of3(S)-isopropyl-5(S)-{1(S)-azido-4-methyl-3(S)-[(4(S)-benzyl-oxazolidin-2-on-3-yl)-carbonyl]-pentyl}-tetrahydrofuran-2-onein 500 ml of tetrahydrofuran. The reaction mixture is stirred for onehour at 5° C. and for 150 minutes at room temperature, and then 750 mlof aqueous 1M sodium sulfite solution are added at 3° C. over a periodof 30 minutes and the mixture is stirred for a further 30 minutes atroom temperature. The reaction mixture is then freed of tetrahydrofuranby concentration, and the aqueous solution is washed three times with1200 ml of ethyl acetate, the organic phases being back-extracted threetimes with 100 ml of 0.1N sodium hydroxide. The combined aqueous phasesare adjusted to pH 1-2 with approximately 200 ml of 4N hydrochloric acidand are extracted with 3×1200 ml of ethyl acetate. The organic phasesare combined, dried over magnesium sulfate and concentrated byevaporation, yielding the crude product which, for the purpose ofcyclisation of the opened lactone, is dissolved in 500 ml of toluene andstirred for 2 hours at 50° C. with approximately 1 g of molecular sieveand approximately 1 g of p-toluenesulfonic acid. Filtration,concentration by evaporation and purification of the residue by means ofFC (hexane/ethyl acetate/glacial acetic acid=30:60:1) yield the titlecompound, which crystallises spontaneously: m.p.=56°-58° C.; R_(f)(hexane/ethyl acetate/glacial acetic acid=30:60:1)=0.62; HPLC R_(t)=14.46 minutes; FAB-MS (M+H)⁺ =298.

l)3(S)-Isopropyl-5(S)-(1(S)-azido-3(S)-isopropyl-4-oxo-butyl)-tetrahydrofuran-2-one

1.45 ml of oxalyl chloride are added dropwise at 0° C., with stirring,within a period of 10 minutes, to a solution of 1.7 g of3(S)-isopropyl-5(S)-(1(S)-azido-3(S)-carboxy-4-methyl-pentyl)-tetrahydrofuran-2-onein 20 ml of toluene. 0.03 ml of dimethylformamide is then added, and thetemperature is then increased to 37° C. within a period of 30 minutes.The reaction mixture is stirred for 2 hours at 37° C. and is thenclarified by filtration and concentrated by evaporation under reducedpressure at a bath temperature of 30° C. The residue is twice dissolvedin 10 ml of toluene and concentrated by evaporation again in the samemanner. The crude acid chloride so obtained is dissolved in 5 ml oftetrahydrofuran, and 16 ml of a 0.34M solution of NaAlH(O-tert-bu)₃ indiglyme (H. C. Brown et al., J. Org. Chem. (1992) 58.472) are addedthereto at -75° C. within a period of 30 minutes. The reaction mixtureis stirred for 70 minutes at -75° C., and then a solution of 0.385 ml ofglacial acetic acid in 1 ml of tetrahydrofuran is added dropwise at thesame temperature, followed by 2.1 ml of saturated NH₄ Cl solution andthen 20 ml of diethyl ether. The reaction mixture is brought to roomtemperature and is partitioned between diethyl ether and water/saturatedsodium chloride solution. The organic phases are combined, dried overmagnesium sulfate and concentrated by evaporation, and the residue ispurified by means of FC (hexane/ethyl acetate=95:5), yielding the titlecompound: R_(f) (hexane/ethyl acetate=2:1)=0.55; HPLC R_(t) =16.41minutes.

EXAMPLE 825(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-morpholinoethyl)amide hydrochloride

30 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-2-morpholino-ethyl)amide are dissolved in 1.5 ml of a 4Nsolution, cooled to 0° C., of hydrochloric acid in dioxane, and themixture is then stirred for 10 minutes at 0° C. The reaction mixture isconcentrated to dryness by evaporation under reduced pressure and atroom temperature. Purification of the residue by means of FC (5 g ofsilica gel, dichloromethane/methanol=98:2) yields the title compound:R_(f) (dichloromethane/methanol=8:2)=0.20; R_(t) =10.43 minutes; FAB-MS(M+H)⁺ =610.

The starting material is prepared as follows:

a) 2-(3-Methoxypropyloxy)-phenol

A solution of 22 g of pyrocatechol in 80 ml of dimethylformamide isadded at room temperature, within a period of 30 minutes, to asuspension of 8.4 g of NaH (60% dispersion in mineral oil) in 300 ml ofdimethylformamide, and the mixture is stirred for one hour at roomtemperature. A solution of 49.3 g of 3-bromopropyl methyl ether in 80 mlof dimethylformamide is then added dropwise. The reaction mixture isstirred for a further 80 hours at room temperature and is thenconcentrated by evaporation under reduced pressure at a bath temperatureof 30° C. The residue is partitioned between diethyl ether and water.The combined organic phases are dried over magnesium sulfate andconcentrated by evaporation, and the residue is purified by FC (100 g ofsilica gel, hexane/dichloromethane=5:95), yielding the title compound:R_(f) (dichloromethane/diethyl ether=96:4)=0.35; HPLC R_(t) =11.2minutes.

b) 4-Bromo-2-(3-methoxypropyloxy)-phenol

6.9 g of tetrabutylammonium tribromide are added in portions, at roomtemperature, to a solution of 2.6 g of 2-(3-methoxypropyloxy)-phenol in60 ml of dichloromethane and 40 ml of methanol, and the mixture is thenstirred for 30 minutes. The reaction mixture is concentrated byevaporation and the residue is partitioned between diethyl ether andwater. The combined organic phases are dried over magnesium sulfate andconcentrated by evaporation, and the residue is purified by FC (700 g ofsilica gel, dichloromethane/diethyl ether=98:2), yielding the titlecompound: R_(f) (dichloromethane/diethyl ether=97:3)=0.50; HPLC R_(t)=14.32 minutes; FAB-MS (M+H)⁺ =262.

c) 4-(3-Benzyloxypropyloxy)-3-(3-methoxypropyloxy)-bromobenzene

A mixture of 4 g of 4-bromo-2-(3-methoxypropyloxy)-phenol, 2.3 g ofpotassium carbonate, 3.8 g of benzyl (3-bromopropyl) ether, a spatulatip of NaI and 15 ml of acetonitrile is stirred under reflux for 30hours. The reaction mixture is filtered and the filtrate is concentratedby evaporation. The residue is partitioned between ethyl acetate andwater. The organic phases are combined, dried over magnesium sulfate andconcentrated by evaporation, and the residue is purified by means of FC(hexane/ethyl acetate=95:5), yielding the title compound: R_(f)(hexane/ethyl acetate=9:1)=0.15; HPLC R_(t) =20.66 minutes.

d)3(S)-Isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-hydroxy-4-[4-(3-benzyloxy-propyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one

1.3 ml of a 0.9M solution of butyllithium in hexane are slowly addeddropwise to a solution, stirred at -75° C., of 500 mg of4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-bromobenzene in 2 ml oftetrahydrofuran. The reaction mixture is stirred for 20 minutes at -75°C., and then a suspension of magnesium bromide, freshly prepared from44.5 mg of magnesium powder and 0.158 ml of 1,2-dibromoethane in 3 ml oftetrahydrofuran at room temperature, is added dropwise. The reactionmixture is stirred for a further 30 minutes at -75° C., and then asolution of 172 mg of3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxo-butyl]-tetrahydrofuran-2-onein 2 ml of tetrahydrofuran is added dropwise. The mixture is againstirred for 30 minutes at -75° C., and then 1.2 ml of saturated ammoniumchloride solution are added dropwise at the same temperature. Thereaction mixture is brought to room temperature and is then extractedthree times with ethyl acetate. The organic phases are washed with water(2x) and saturated sodium chloride solution (1x), dried over magnesiumsulfate, combined and concentrated by evaporation, and the residue ispurified by means of FC (2×30 g of silica gel, hexane/ethylacetate=6:2), yielding the title compound: R_(f) (hexane/ethylacetate=2:1)=0.23; HPLC R_(t) =20.27 and 21.07 minutes(diastereoisomeric mixture); FAB-MS M⁺ =611.

e)3(S)-Isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-acetoxy-4-[4-(3-benzyloxy-propyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one

A solution of 144 mg of3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-hydroxy-4-[4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-onein 1.8 ml of acetic anhydride and 0.057 ml of pyridine is stirred for 30hours at room temperature and is then concentrated to dryness byevaporation at room temperature and under reduced pressure. The residueis partitioned between dichloromethane (3x) and water/saturated sodiumchloride solution (3x). The organic phases are combined, dried overmagnesium sulfate and concentrated by evaporation, and the residue ispurified by means of FC (hexane/ethyl acetate=4:1), yielding the titlecompound: R_(f) (hexane/ethyl acetate=2:1)=0.38 and 0.33; HPLC R_(t)=21.76 and 21.82 minutes (diastereoisomeric mixture); FAB-MS M⁺ =653,(M+Na)⁺ =676.

f)3(S)-Isopropyl-5(S)-{1(S)-amino-3(S)-isopropyl-4-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one

A solution of 151 mg of3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-acetoxy-4-[4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-onein 10 ml of ethanol is hydrogenated under normal pressure and at roomtemperature in the presence of 70 mg of PdO for 170 hours. The reactionmixture is filtered and concentrated by evaporation, and the residue isdissolved in 10 ml of ethanol and is again hydrogenated for 24 hours inthe presence of 140 mg of PdO under normal pressure and at roomtemperature. Filtration and concentration by evaporation yield the titlecompound in the form of a crude product: R_(f)(dichloromethane/methanol)=0.32; HPLC R_(t) =11.72 minutes; FAB-MS(M+H)⁺ =480. The compound is used in the next step without beingpurified.

g)3(S)-Isopropyl-5(S)-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-(3-hydroxy-propyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one

To a solution, stirred at 0° C., of 106 mg of3(S)-isopropyl-5(S)-{1(S)-amino-3(S)-isopropyl-4-[4-(3-hydroxy-propyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-onein 4.5 ml of dichloromethane there are added dropwise a solution of 0.07ml of N-ethyldiisopropylamine in 0.1 ml of dichloromethane and then asolution of 77 mg of di-tert-butyl dicarbonate in 0.4 ml ofdichloromethane. The reaction mixture is then brought to roomtemperature, is stirred at room temperature for 20 hours and is thenconcentrated to dryness by evaporation. Purification of the residue bymeans of FC (50 g of silica gel, dichloromethane/methanol=98:2) yieldsthe title compound: R_(f) (dichloromethane/methanol=95:5)=0.34; HPLCR_(t) =19.07 minutes; FAB-MS M⁺ =579, (M+Na)⁺ =602.

h)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diispropyl-8-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-2-morpholinoethyl)amide

A mixture of 84 mg of3(S)-isopropyl-5(S)-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one,0.6 ml of 4-(2-aminoethyl)-morpholine and 0.025 ml of glacial aceticacid is stirred for 16 hours at room temperature and for 6 hours at 45°C. and is then partitioned between diethyl ether (2x) and saturatedNaHCO₃ solution (ix) and water (2x). The organic phases are combined,dried over magnesium sulfate and concentrated by evaporation, and theresidue is purified by means of FC (5 g of silica gel,dichloromethane/methanol=98:2), yielding the title compound: R_(f)(dichloromethane/methanol=95:5)=0.16; HPLC R_(t) =14.49 minutes; FAB-MS(M+H)⁺ =710.

EXAMPLE 835(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide semifumarate

20 g of ice and 12 ml of 2N NaOH are added in succession to a stirredsolution of 2.35 g of5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide hydrochloride (Example137) in 20 ml of water, and the mixture is then extracted with 3×50 mlof tert-butyl methyl ether. The combined organic phases are dried withmagnesium sulfate and concentrated by evaporation. 0.232 g of fumaricacid is added to the evaporation residue in 25 ml of methanol. Themixture is stirred until a clear solution has formed and is thenconcentrated by evaporation. The residue is crystallised from 100 ml ofacetonitrile/ethanol=95:5. The crystals are filtered off with suctionand dried at 60° C. The title compound is obtained in the form of awhite powder having a melting point of 95°-104° C.

EXAMPLE 845(S)-Amino-2(S),7(S)-diisopropyl-4(S)-hydroxy-8-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-octanoicacid [N-2-(morpholin-4-yl)-ethyl]-amide dihydrochloride

A 4N hydrochloric acid solution in dioxane (20 ml) is added at 0°-5° C.to 768 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-octanoicacid [N-2-(morpholin-4-yl)-ethyl]-amide, and the mixture is then stirredfor one hour. The solvent is then removed by lyophilisation under a highvacuum, the residue is dissolved in anhydrous dichloromethane andfiltered over cotton wool, and the filtrate is concentrated. A smallamount of 4N hydrochloric acid in dioxane is again added to the residue,the resulting solution is lyophilised, and the residue is dried under ahigh vacuum. The title compound is obtained in the form of a whiteamorphous solid: R_(f) (dichloromethane/methanol/conc.ammonia=9:1:0.1)=0.23; HPLC R_(t) =14.5 minutes; FAB-MS (M+H)⁺ =592.

The starting materials are prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-octanoicacid [N-2-(morpholin-4-yl)-ethyl]-amide

A solution of 756 mg of3(S)-isopropyl-5(S)-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-butyl}-tetrahydrofuran-2-onein 4 ml of 4-(2-aminoethyl)-morpholine and 0.23 ml of glacial aceticacid is stirred for 4 hours at 65° C. and is then concentrated byevaporation. The residue is partitioned between diethyl ether (30 ml)and a saturated sodium hydrogen carbonate solution (10 ml), the aqueousphase is extracted with diethyl ether (2×30 ml), and the combinedorganic phases are dried over magnesium sulfate and concentrated.Purification of the residue by means of FC (70 g of silica gel,dichloromethane/methanol/conc. ammonia=98:2:1 after 96:4:1) yields thetitle compound in the form of a white foam: R_(f)(dichloromethyane/methanol/conc. ammonia=9:1:0.1)=0.43; HPLC R_(t) =19.8minutes.

b)3(S)-Isopropyl-5(S)-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-butyl}-tetrahydrofuran-2-one

A solution of 1.24 g of3(S)-isopropyl-5(S)-{4(R,S)-acetoxy-1(S)-azido-3(S)-isopropyl-4(R,S)-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-butyl}-tetrahydrofuran-2-onein 25 ml of ethanol is hydrogenated for a period of 28 hours in thepresence of 2.4 g of 5% PdO/C (Engelhardt) at room temperature and undernormal pressure. The reaction mixture is filtered over Celite 545 andwashed with ethanol, and the residue obtained after concentration isdried under a high vacuum. The product so obtained (843 mg) is dissolvedin 20 ml of dichloromethane, and 0.58 ml of N-diisopropylethylamine anda solution of 638 mg of di-tert-butyl dicarbonate in 5 ml ofdichloromethane are added thereto in succession at 0°-5° C. The mixtureis stirred at room temperature overnight, and then the solvent isremoved in vacuo and the crude product is purified by means of FC (60 gof silica gel, hexane/ethyl acetate/conc. ammonia=80:20:1). The titlecompound is obtained in the form of a colourless oil: R_(f)(hexane/ethyl acetate/conc. ammonia=50:50:1)=0.90; HPLC R_(t) =26.2minutes.

c)3(S)-Isopropyl-5(S)-{4(R,S)-acetoxy-1(S)-azido-3(S)-isopropyl-4(R,S)-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-butyl}-tetrahydrofuran-2-one

A mixture of 1.15 g of3(S)-isopropyl-5(S)-{4(R,S)-hydroxy-1(S)-azido-3(S)-isopropyl-4(R,S)-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-butyl}-tetrahydrofuran-2-one,11 ml of acetic anhydride and 0.55 ml of pyridine is stirred overnightat room temperature. The reaction mixture is concentrated and theresidue is partitioned between 100 ml of dichloromethane and 20 ml ofwater. The crude product obtained after working up by extraction ispurified by FC (80 g of silica gel, hexane/ethyl acetate=2:1). The titlecompound is obtained in the form of a yellowish oil: R_(f) (hexane/ethylacetate=2:1)=0.66.

d)3(S)-Isopropyl-5(S)-{4(R,S)-hydroxy-1(S)-azido-3(S)-isopropyl-4(R,S)-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-butyl}-tetrahydrofuran-2-one

In a manner analogous to that described in Example 185c),4-tert-butyl-3-(3-methoxy-propoxy)-bromobenzene (2.35 g), dissolved in60 ml of tetrahydrofuran, is reacted with 4.86 ml of a 1N n-butyllithiumsolution (in hexane) and then with a suspension of magnesium bromide in20 ml of tetrahydrofuran (prepared from 380 mg of magnesium powder and1.35 ml of 1,2-dibromoethane in). A solution of 1.46 g of3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-onein 6 ml of tetrahydrofuran is added dropwise to the resulting suspensionat -70° C. over a period of 20 minutes, and the mixture is then stirredfor a further one hour. After working up by extraction, the crudeproduct is purified by FC (300 g of silica gel, hexane/ethyl acetate=5:1after 3:1). The title compound is obtained in the form of a pale yellowoil: R_(f) (hexane/ethyl acetate=2:1)=0.57; HPLC R_(t) =22.9 and 24.1minutes (diastereoisomeric mixture).

e) 4-Tert-butyl-3-(3-methoxypropoxy)-bromobenzene

A suspension of 2.60 g of 5-bromo-2-tert-butyl-phenol, 4.34 g of3-methoxypropyl bromide and 5.55 g of caesium carbonate in 40 ml ofacetone is stirred at 60° C. overnight. After cooling to roomtemperature, the mixture is filtered and the crude product obtainedafter concentration of the filtrate is purified by means of FC (80 g ofsilica gel, hexane/ethyl acetate=98:2). The title compound is obtainedin the form of an oil: R_(f) (hexane/ethyl acetate=9:1)=0.56.

EXAMPLE 855(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(4-hydroxypiperidin-1-yl)ethyl]amide dihydrochloride

100 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-amide are dissolved in 3 mlof 4N hydrochloric acid in dioxane at 0° C., and the mixture is stirredfor 2 hours at 0° C. The reaction mixture is lyophilised and the titlecompound is obtained: R_(f) (dichloromethane/methanol=8:2)=0.08; HPLCR_(t) =8.85 minutes; FAB-MS (M+H)⁺ =552.

The starting material is prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(4-hydroxypiperidin-1-yl)-ethyl]-amide

102 mg of2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine arestirred for 2 hours at 80° C. The reaction mixture is purified by meansof FC (60 g of silica gel, dichloromethane/methanol=4:1). The titlecompound is obtained: R_(f) (dichloromethane/methanol=4:1)=0.16.

EXAMPLE 865(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2,2-dimethyl-2-morpholino-ethyl)amide dihydrochloride

Analogously to Example 85, the title compound is obtained starting from120 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2,2-dimethyl-2-morpholino-ethyl)-amide: R_(f)(dichloromethane/methanol=9:1)=0.07; HPLC R_(t) =9.22 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 4-(2-amino-1,1-dimethyl-ethyl)-morpholine.

EXAMPLE 875(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(trans-2,6-dimethyl-morpholino)-ethyl]amide dihydrochloride

Analogously to Example 85, the title compound is obtained starting from102 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(trans-2,6-dimethyl-morpholino)-ethyl]amide: R_(f)(dichloromethane/methanol=8:2)=0.27; HPLC R_(t) =9.56 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 4-(2-aminoethyl)-trans-2,6-dimethyl-morpholine.

a) 4-(2-Amino-ethyl)-2,6-(trans)-dimethyl-morpholine

8.20 g of 4-(2-phthaloylaminoethyl)-trans-2,6-dimethyl-morpholine arestirred under reflux for 2 hours in 250 ml of ethyl alcohol with 2.76 mlof hydrazine hydrate. The reaction mixture is diluted with diethyl etherand then clarified by filtration. The filtrate is concentrated, yieldingthe crude title compound: R_(f) (dichloromethane/methanol/conc.ammonia=40:10:1)=0.21.

b) 4-(2-Phthaloylaminoethyl)-trans-2,6-dimethyl-morpholine

10.16 g of N-(2-bromoethyl)-phthalimide and 11.50 g oftrans-2,6-dimethylmorpholine are stirred for 30 minutes at 130° C. Thereaction mixture is then partitioned between ice-water and ethylacetate. The organic phases are concentrated by evaporation and theresidue is purified by means of FC (240 g of silica gel, ethylacetate/hexane=1:2). The title compound is obtained: R_(f) (ethylacetate/hexane=1:2)=0.39.

EXAMPLE 885(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(cis-2,6-dimethyl-morpholino)ethyl]-amide dihydrochloride

Analogously to Example 85, the title compound is obtained starting from97 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(cis-2,6-dimethyl-morpholino)-ethyl]amide: R_(f)(dichloromethane/methanol=8:2)=0.21; HPLC R_(t) =9.38 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 4-(2-amino-ethyl)-cis-2,6-dimethyl-morpholine.

The 4-(2-amino-ethyl)-cis-2,6-dimethyl-morpholine is preparedanalogously to Examples 87 a) and 87 b) from cis-2,6-dimethylmorpholine.

EXAMPLE 895(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-piperidinoethyl)amide dihydrochloride

Analogously to Example 85, the title compound is obtained staging from74 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-piperidinoethyl)amide: R_(f)(dichloromethane/methanol=8:2)=0.09; HPLC R_(t) =9.55 minutes; FAB-MS(M+H)⁺ =536.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and N-(2-piperidinoethyl)amine.

EXAMPLE 905(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(4-methoxypiperidino)-ethyl]-amide dihydrochloride

Analogously to Example 85, the title compound is obtained starting from74 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(4-methoxy-piperidino)ethyl]-amide: R_(f)(dichloromethane/methanol=8:2)=0.12; HPLC R_(t) =9.39 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 1-(2-aminoethyl)-4-methoxypiperidine.

The 1-(2-amino-ethyl)-4-methoxypiperidine is prepared analogously toExamples 87 a) and 87 b) from 4-methoxy-piperidine.

EXAMPLE 915(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-thiomorpholinoethyl)amide dihydrochloride

Analogously to Example 85, the title compound is obtained starting from110 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-thiomorpholino-ethyl)amide: R_(f)(dichloromethane/methanol=8:2)=0.17; HPLC R_(t) =9.53 minutes; FAB-MS(M+H)⁺ =554.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxy-carbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 4-(2-aminoethyl)thiomorpholine.

EXAMPLE 925(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-hydroxypropyl)]amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from110 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-hydroxypropyl)]amide: R_(f)(dichloromethane/methanol=9:1)=0.07; HPLC R_(t) =9.65 minutes; FAB-MS(M+H)⁺ =483.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4-(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 3-amino-1-propanol.

EXAMPLE 935(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-hydroxybutyl)]amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from112 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-hydroxybutyl)]amide: R_(f)(dichloro-methane/methanol=9:1)=0.07; HPLC R_(t) =9.83 minutes; FAB-MS(M+H)⁺ =497.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4-(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 4-amino-1-butanol.

EXAMPLE 945(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-acetoxybutyl)]amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from27 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-acetoxybutyl)]amide: R_(f)(dichloromethane/methanol=9:1)=0.16; HPLC R_(t) =11.53 minutes; FAB-MS(M+H)⁺ =539.

The starting material is prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-acetoxybutyl)]amide

30 ml of triethylamine, 2 mg of 4-(N,N'-dimethylamino)pyridine (DMAP)and 20 ml of acetic anhydride are added at 0° C. to 116 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-hydroxybutyl)]amide (Example 93) in 5 ml of tetrahydrofuran.The reaction solution is stirred for 18 hours at room temperature. Thereaction mixture is partitioned between diethyl ether andwater/saturated sodium chloride solution. The organic phases areconcentrated by evaporation and the residue is purified by FC (40 g ofsilica gel, eluant: dichloromethane/methanol=95:5). The title compoundis obtained: R_(f) (dichloromethane/methanol=9:1)=0.60.

EXAMPLE 955(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-cyanopropyl)]amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from107 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-cyanopropyl)]amide: R_(f)(dichloromethane/methanol=9:1)=0.07; HPLC R_(t) =10.76 minutes; FAB-MS(M+H)⁺ =492.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 4-amino-butyronitrile.

EXAMPLE 965(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-methoxypropyl)]amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from107 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-methoxypropyl)]amide: R_(f)(dichloromethane/methanol=8:2)=0.34; HPLC R_(t) =10.70 minutes; FAB-MS(M+H)⁺ =497.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 3-methoxy-propylamine.

EXAMPLE 975(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-acetylamino-ethyl)]amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from82 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-acetylamino-ethyl)]amide: R_(f)(dichloromethane/methanol=8:2)=0.17; HPLC R_(t) =9.54 minutes; FAB-MS(M+H)⁺ =510.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxy-carbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and N-acetyl-ethylenediamine.

EXAMPLE 985(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(2-pyridyl)-ethyl]}-amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from118 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(2-pyridyl)-ethyl]}-amide: R_(f)(dichloromethane/methanol=9:1)=0.09; HPLC R_(t) =8.88 minutes; FAB-MS(M+H)⁺ =530.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 2-(2-aminoethyl)-pyridine.

EXAMPLE 995(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N'-oxomorpholino)ethyl]-amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from82 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N'-oxomorpholino)ethyl]amide: R_(f)(dichloromethane/methanol=8:2)=0.07; HPLC R_(t) =9.04 minutes; FAB-MS(M+H)⁺ =554.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 4-(2-aminoethyl)-N-oxo-morpholine.

The starting material is prepared as follows:

a) 4-(2-Aminoethyl)-N-oxo-morpholine

2.8 g of 4-(2-benzyloxycarbonylaminoethyl)-N-oxo-morpholine arehydrogenated in the presence of 0.30 g of 10% Pd/C in methanol for 10minutes at room temperature and under normal pressure. The reactionmixture is filtered and concentrated by evaporation. The crude titlecompound is obtained: ¹ H-NMR (CD₃ OD), δ(ppm)=4.90 (2H, s), 4.20 (1H,m), 3.87-2.80 (10H, m), 2.50 (1H, m)

b) 4-(2-Benzyloxycarbonylaminoethyl)-N-oxo-morpholine

6 portions, each of 1.48 ml, of 30% hydrogen peroxide are added at 60°C., with stirring, at intervals of 12 hours, to 10.6 g of4-(2-benzyloxycarbonylaminoethyl)-morpholine in 12 ml of methanol.Saturated sodium sulfite solution is added carefully to the cooledreaction mixture until the excess peroxide has been destroyed. Themethanol is evaporated off, and the resulting suspension is taken up inethyl acetate/methanol 99:1. The mixture is dried with magnesium sulfateand is filtered, and the filtrate is concentrated by evaporation.Crystallisation from ethyl acetate yields the title compound: R_(f)(dichloromethane/methanol=8:2)=0.17; m.p. 163° C.

EXAMPLE 1005(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(tert-butylsulfonyl)-propyl]}-amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from110 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(tert-butylsulfonyl)-propyl]}-amide: R_(f) (ethylacetate/methanol/conc. ammonia=80:15:5)=0.45; HPLC R_(t) =11.27 minutes;FAB-MS (M+H)⁺ =587.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 3-amino-1-(tert-butylsulfonyl)propane.

The starting material is prepared as follows:

a) 3-Amino-1-(tert-butylsulfonyl)-propane

1.0 g of 3-aminopropyl-(tert-butylsulfonyl)-propane is dissolved at 0°C. in 30 ml of water. 2.14 g of potassium permanganate and 2 ml of 4Nhydrochloric acid in 30 ml of water are added in succession, and themixture is stirred overnight at 0° C. The dark suspension is filteredoff and washed with 100 ml of hot water. 50 ml of toluene are added tothe filtrate, and the mixture is concentrated. The precipitated whitecrystals are purified by means of FC (10 g of silica gel, ethylacetate/methanol/cone. ammonia=80:15:5). The title compound is obtained:R_(f) (ethyl acetate/methanol/conc. ammonia=80:15:5)=0.20.

EXAMPLE 1015(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3;(ethylsulfonyl)-propyl]}-amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from44 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(ethylsulfonyl)-propyl]}-amide: R_(f) (ethylacetate/methanol/conc. ammonia=80:15:5)=0.26; HPLC R_(t) =10.40 minutes;FAB-MS (M+H)⁺ =559.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 3-amino-1-(ethylsulfonyl)propane.

The starting material is prepared as follows:

a) 3-Amino-1-(ethylsulfonyl)-propane

1.0 g of 3-aminopropyl-ethyl sulfide is placed in 35 ml of methanol at0° C.; 15.5 g of oxone in 35 ml of water are added and the mixture isstirred at 0° C. for 4 hours. 200 ml of water are added and the mixtureis extracted with 3 x 150 ml of dichloromethane. The organic extractsare concentrated by evaporation and purified by FC (10 g of silica gel,ethyl acetate/methanol/conc. ammonia=80: 15:5). The title compound isobtained: R_(f) (ethyl acetate/methanol/conc. ammonia=80: 15:5)=0.15.

EXAMPLE 1025(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(ethylsulfonyl)-ethyl]}-amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from90 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(ethylsulfonyl)-ethyl]}-amide: R_(f) (ethylacetate/methanol/conc. ammonia=80:15:5)=0.39; HPLC R_(t) =10.50 minutes;FAB-MS (M+H)⁺ =545.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 2-amino-1-(ethylsulfonyl)ethane.

EXAMPLE 1035(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N-butylsulfonyl)-ethyl]}-amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from67 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N-butylsulfonyl)-ethyl]}-amide: R_(f) (ethylacetate/methanol/conc. ammonia=80: 15:5)=0.41; HPLC R_(t) =12.52minutes; FAB-MS (M+H)⁺ =588.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 2-aminoethyl-(N-butyl)sulfonamide.

EXAMPLE 1045(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylsulfonyl)-ethyl]}-amide hydrochloride

Analogously to Example 85, the title compound is obtained starting from120 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylsulfonyl)-ethyl]}-amide: R_(f) (ethylacetate/methanol/conc. ammonia=80:15:5)=0.43; HPLC R_(t) =11.03 minutes;FAB-MS (M+H)⁺ =560.

The starting material is prepared analogously to Example 85 a) from2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one(Example 105 e) and 2-aminoethyl-(N,N-dimethyl)sulfonamide.

EXAMPLE 1055(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-carbamoyl-propyl)]-amide hydrochloride

84 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-carbamoyl-propyl)]-amide are dissolved in 3 ml of 4Nhydrochloric acid in dioxane at 0° C. and the mixture is stirred for 2hours at 0° C. The reaction mixture is lyophilised. The title compoundis obtained: R_(f) (dichloromethane/methanol=9:1)=0.04; HPLC R_(t) =9.44minutes; HR FAB-MS (M+H)⁺ =510.

The starting materials are prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-carbamoyl-propyl)]-amide

50 mg of tetrabutylammonium fluoride trihydrate are added to 115 mg of5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-carbamoyl-propyl)]-amide in 4 ml of dimethylformamide at 0°C. The reaction mixture is stirred for a further 5 hours at roomtemperature and then concentrated by evaporation. 20 ml of saturatedsodium hydrogen carbonate solution are added to the evaporation residueand the mixture is extracted repeatedly with ethyl acetate. The organicphases are washed with saturated sodium chloride solution andconcentrated by evaporation. The residue is purified by means of FC (18g of silica gel, dichloromethane/methanol=9:1). The title compound isobtained: R_(f) (dichloromethane/methanol=9:1): 0.24.

b)5(S)-Tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-carbamoyl-propyl)]-amide

67 μl of triethylamine, 34 mg of 4-aminobutyric acid amide hydrochlorideand 38 μl of cyanophosphonic acid diethyl ester are added in successionto 128 mg of5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid in 8 ml of dimethylformamide at 0° C. The reaction mixture isstirred for a further 18 hours at room temperature. The reaction mixtureis concentrated by evaporation and 20 ml of 10% citric acid solution andice are added to the residue. The mixture is extracted repeatedly withethyl acetate and the organic phases are then washed with saturatedsodium hydrogen carbonate solution and saturated sodium chloridesolution. After concentration by evaporation, the residue is purified bymeans of FC (70 g of silica gel, dichloromethane/methanol=9:1). Thetitle compound is obtained: R_(f) (dichloromethane/methanol=9:1)=0.38.

c)5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid

4.45 g of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (crude) are stirred in 45 ml of dimethylformamide with 2.36 g oftert-butyldimethylsilyl chloride and 2.03 g of imidazole for 6 days atroom temperature. The mixture is concentrated by evaporation and theresidue is partitioned between 10% citric acid solution and ethylacetate. The organic phase is concentrated and stirred in 20 ml oftetrahydrofuran, 8 ml of water and 20 ml of acetic acid at roomtemperature for 16 hours. After concentration by evaporation, ice/wateris added to the residue and the mixture is then extracted with ethylacetate. The title compound is obtained from the organic phase after FC(260 g of silica gel, ethyl acetate/hexane=1:1): R_(f) (ethylacetate/hexane=1:1)=0.32.

d)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid

28.5 ml of 1N lithium hydroxide solution are added to 3.6 g of2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-onein 210 ml of 1,2-dimethoxyethane/water (2:1) at room temperature. Thereaction mixture is stirred at room temperature for a further 1 hour andthen concentrated by evaporation. Ice and 10% aqueous citric acidsolution are added to the residue. Repeated extraction with chloroformyields the crude title compound: R_(f) (ethyl acetate/hexane=1:1)=0.05;HPLC R_(t) =16.41 minutes.

e)2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one

2.02 g of p-toluenesulfonic acid (monohydrate) are added to 5.6 g of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)-amide (Example 32) in 240 ml of chloroform at roomtemperature and the mixture is stirred at room temperature for a further18 hours. The reaction mixture is concentrated by evaporation and theresidue is partitioned between diethyl ether and 0.1N hydrochloric acid.The organic phases are concentrated by evaporation and the titlecompound is obtained from the residue after FC (160 g of silica gel,eluant: ethyl acetate/hexane 1:1): R_(f) (ethylacetate/hexane=2:1)=0.47; m.p. 86°-87° C.

EXAMPLE 1065(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(1H-tetrazol-5-yl)-propyl]}-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from47 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(1H-tetrazol-5-yl)-propyl]}-amide and after lyophilisation:R_(f) (dichloromethane/methanol=8:2)=0.46; HPLC R_(t) =9.97 minutes;FAB-MS (M+H)⁺ =535.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 3-(1H-tetrazol-5-yl)-propylamine.

EXAMPLE 1075(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(1H-imidazol-5-yl)-propyl]}-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from43 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(1H-imidazol-5-yl)-propyl]}-amide and after lyophilisation:R_(f) (dichloromethane/methanol=8:2)=0.13; HPLC R_(t) =8.83 minutes;FAB-MS (M+H)⁺ =533.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 3-(1H-imidazol-5-yl)-propylamine.

EXAMPLE 1085(S)-Amino-4(S)-hydroxy-7-(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-3-(3-methyl-1,2,4-oxadiazol-5-yl)-propyl]}-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from140 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(3-methyl-1,2,4-oxadiazol-5-yl)-propyl]}-amide and afterlyophilisation: R_(f) (dichloromethane/methanol=9:1)=0.12; HPLC R_(t)=11.05 minutes; FAB-MS (M+H)⁺ =549.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 3-(3-methyl-1,2,4-oxadiazol-5-yl)-propylamine.

a) 3-(3-Methyl-1,2,4-oxadiazol-5-yl)-propylamine

272 mg of 3-methyl-5-[3-(N-phthaloylamino)propyl]-1,2,4-oxadiazole in 10ml of ethyl alcohol are stirred for 2 hours under reflux with 146 ml ofhydrazine hydrate. The reaction mixture is diluted with diethyl etherand then clarified by filtration. The filtrate is concentrated byevaporation and yields the crude title compound: R_(f)(dichloromethane/methyl alcohol/conc. ammonia=40:10:1)=0.37.

b) 3-Methyl-5-[3-(N-phthaloylamino)propyl]-1,2,4-oxadiazole

0.84 g of sodium hydride dispersion (80% ) is added to 2.08 g ofacetamidoxime in 200 ml of tetrahydrofuran at room temperature and themixture is stirred at 60° C. for 2 hours. A solution of 2.47 g of4-(N-phthaloylamino)butyric acid methyl ester in 30 ml oftetrahydrofuran is then added and stirring is continued at 60° C. for afurther 3 hours. The reaction mixture is poured onto 1N hydrochloricacid/ice and extracted repeatedly with ethyl acetate. The dried organicphases are concentrated by evaporation and the residue is boiled in 60ml of xylene for 3 hours on a water-separator. The solvent is evaporatedoff and the title compound is obtained from the residue after FC (40 gof silica gel, ethyl acetate/hexane=1:1): R_(f) (ethylacetate/hexane=1:1)=0.26.

EXAMPLE 1095(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-aminopropyl)]-amide dihydrochloride

Analogously to Example 105, the title compound is obtained starting from125 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-tert-butoxycarbonylamino-propyl)]-amide and afterlyophilisation: R_(f) (dichloromethane/methanol/conc.ammonia=40:10:1)=0.08; HPLC R_(t) =6.48 minutes; FAB-MS (M+H)⁺ =482.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 3-tert-butoxycarbonylamino-propylamine.

EXAMPLE 1105(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-dimethylamino-ethyl)]-amide dihydrochloride

Analogously to Example 105, the title compound is obtained starting from38 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-dimethylamino-ethyl)]-amide and after lyophilisation: R_(f)(dichloromethane/methanol/conc. ammonia=350:50:1)=0.03; HPLC R_(t) =8.61minutes; FAB-MS (M+H)⁺ =496.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 2-dimethylaminoethylamine.

EXAMPLE 1115(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-morpholinoethyl)amide dihydrochloride

Analogously to Example 105, the title compound is obtained starting from70 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-morpholinoethyl)amide and after lyophilisation: R_(f)(dichloromethane/methanol/conc. ammonia=350:50:1)=0.15; HPLC R_(t) =8.74minutes; FAB-MS (M+H)⁺ =538.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 4-(2-aminoethyl)-morpholine.

EXAMPLE 1125(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-morpholinopropyl)amide dihydrochloride

Analogously to Example 105, the title compound is obtained starting from37 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-morpholinopropyl)amide and after lyophilisation: R_(f)(dichloromethane/methanol/conc. ammonia=350:50:1)=0.11; HPLC R_(t) =8.68minutes; FAB-MS (M+H)⁺ =552.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 4-(3-aminopropyl)-morpholine.

EXAMPLE 1135(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(1,1-dioxothiomorpholino )ethyl]amide dihydrochloride

Analogously to Example 105, the title compound is obtained starting from100 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(1,1-dioxothiomorpholino)ethyl]-amide and afterlyophilisation: R_(f) (dichloromethane/methanol=8:2)=0.30; HPLC R_(t)=9.29 minutes; FAB-MS (M+H)⁺ =586.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 2-(1,1-dioxothiomorpholino)-ethylamine.

EXAMPLE 1145(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-ethoxycarbonylethyl)amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from32 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-ethoxycarbonyl-ethyl)]-amide and after lyophilisation: R_(f)(dichloromethane/methanol=9:1)=0.17; HPLC R_(t) =11.31 minutes; FAB-MS(M+H)⁺ =525.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and β-alanine ethyl ester hydrochloride.

EXAMPLE 1155(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carboxy-ethyl)]-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from60 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carboxy-ethyl)]-amide and after lyophilisation: R_(f)(dichloromethane/methanol=8:2)=0.28; HPLC R_(t) =9.74 minutes; FAB-MS(M+H)⁺ =497.

The starting material is prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carboxyethyl)]-amide

70 mg of5(S)-tert-butoxyamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-ethyloxy-carbonylethyl)]-amide (Example 114) are stirred in 2ml of methanol with 224 μl of 1N sodium hydroxide at room temperaturefor 18 hours. After evaporation of the methanol, 250 μl of 1Nhydrochloric acid are added and the product is extracted with ethylacetate. The organic phase is concentrated by evaporation and theresidue is purified by means of FC (10 g of silica gel, eluant:dichloromethane/methanol=8:2). The title compound is obtained: R_(f)(dichloromethane/methanol=9:1)=0.12.

EXAMPLE 1165(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-methoxycarbonyl-ethyl)]-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from90 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-methoxycarbonyl-ethyl)]-amide and after lyophilisation: R_(f)(dichloromethane/methanol=9:1)=0.13; HPLC R_(t) =10.80 minutes; FAB-MS(M+H)⁺ =525.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 4-aminobutyric acid methyl ester hydrochloride.

EXAMPLE 117(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-carboxypropyl)]-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from38 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-carboxypropyl)]-amide and after lyophilisation: R_(f)(dichloromethane/methanol=8:2)=0.55; HPLC R_(t) =9.85 minutes; FAB-MS(M+H)⁺ =511.

The starting material is prepared as follows:

5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(3-carboxypropyl)]-amide

Analogously to Example 115 a), the title compound is prepared from5(S)-tert-butoxycarbonyl-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-methyloxycarbonylpropyl)]-amide (Example 116).

EXAMPLE 1185(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoylethyl)]-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from93 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoylethyl)]-amide and after lyophilisation: R_(f)(dichloromethane/methanol=8:2)=0.15; HPLC R_(t) =9.33 minutes; FAB-MS(M+H)⁺ =496.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 3-aminopropionic acid amide hydrochloride.

EXAMPLE 1195(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-carbamoylbutyl)-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from85 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(4-carbamoylbutyl)]-amide and after lyophilisation: R_(f)(dichloromethane/methanol=8:2)=0.20; HPLC R_(t) =9.72 minutes; FAB-MS(M+H)⁺ =524.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 5-aminopentanoic acid amide hydrochloride.

EXAMPLE 1205(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[3-(N-methylcarbamoyl)propyl]amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from89 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[3-(N-methylcarbamoyl)propyl]amide and after lyophilisation:R_(f) (dichloromethane/methanol=9:1)=0.04; HPLC R_(t) =9.74 minutes;FAB-MS (M+H)⁺ =524.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 4-amino-N-methyl-butyric acid amidehydrochloride.

EXAMPLE 1215(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{3-[N-(2-methoxyethyl)carbamoyl]propyl}-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from92 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{3-[N-(2-methoxyethyl)carbamoyl]propyl}-amide and afterlyophilisation: R_(f) (dichloromethane/methanol=8:2)=0.28; HPLC R_(t)=10.14 minutes; FAB-MS (M+H)⁺ =568.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 4-aminobutyric acid N-(2-methoxyethyl)amidehydrochloride.

The starting material is prepared as follows:

4-Aminobutyric acid N-(2-methoxyethyl)amide hydrochloride

2.95 g of 4-benzyloxycarbonylaminobutyric acid N-(2-methoxyethyl)amideare hydrogenated in the presence of 0.24 g of 10% Pd/C in 150 ml ofmethanol and 100 ml of 0.1N hydrochloric acid for 2 hours at roomtemperature and under normal pressure. The reaction mixture is filteredand concentrated by evaporation. The crude title compound is obtained: ¹H NMR (CD₃ OD), δ(ppm)=4.92(4H, s), 3.53-3.20 (4H, m), 3.34 (3H, 2.96(2H, t, J=12 Hz), 2.37 (2H, t, J=12 Hz), 1.93 (2H, m).

b) 4-Benzyloxycarbonylaminobutyric acid N-(2-methoxyethyl)amide 5.02 gof 4-benzyloxycarbonylaminobutyric acid methyl ester are stirred underreflux in 35 ml of ethanol with 15 ml of 2-methoxyethylamine for 5 days.The reaction mixture is concentrated by evaporation and the residue ispurified by means of FC (240 g of silica gel,dichloromethane/methanol=95:5). The title compound is obtained: R_(f)(dichloromethane/methanol=95:5)=0.33.

EXAMPLE 1225(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(4-morpholino-4-oxo-butyl)amide hydrochloride

Analogously to Example 105, the title compound is obtained staring from110 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(4-morpholino-4-oxo-butyl)amide and after lyophilisation: R_(f)(dichloromethane/methanol=9:1)=0.06; HPLC R_(t) =10.17 minutes; FAB-MS(M+H)⁺ =580.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 4-aminobutyric acid N'-(4-morpholino)amidehydrochloride.

EXAMPLE 1235(S)-Amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide hydrochloride

Analogously to Example 105, the title compound is obtained starting from66 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide and afterlyophilisation: R_(f) (dichloromethane/methanol=8:2)=0.27; HPLC R_(t)=12.10 minutes; FAB-MS (M+H)⁺ =524.

The starting material is prepared analogously to Example 105 a) and 105b) from5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (Example 105 c) and 3-amino-2,2-dimethyl-propionic acid amidehydrochloride.

EXAMPLE 1245(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-morpholinoethyl)amide dihydrochloride

3.09 g of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-morpholinoethyl)amide are dissolved in 40 ml of 4Nhydrochloric acid in dioxane at 0° C. and the solution is stirred at 0°C. for 2 hours. The reaction mixture is lyophilised and the titlecompound is obtained: R_(f) (dichloromethane/methanol=8:2)=0.27; HPLCR_(t) =9.52 minutes; HR FAB-MS (M+H)⁺ =566.

The starting materials are prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-morpholino-ethyl)amide

1.30 g of p-toluenesulfonic acid (monohydrate) are added to 4.18 g of3-tert-butoxycarbonyl-5(S)-{2(S)-[N-(2-morpholino-ethyl)carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidinein 160 ml of methanol at 0° C. The reaction solution is stirred at roomtemperature for a further 18 hours. After evaporation of the solvent,200 ml of 0.1N sodium hydroxide are added to the residue and extractionis carried out with dichloromethane. The organic extracts areconcentrated by evaporation and purified by FC (230 g of silica gel,dichloromethane/methanol=95:5). The title compound is obtained: R_(f)(dichloromethane/methanol=9:1)=0.55.

b)3-Tert-butoxycarbonyl-5(S)-{2(S)-[N-(2-morpholino-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

1.09 ml of triethylamine, 1.02 ml of 4-(2-aminoethyl)-morpholine and1.19 ml of cyanophosphonic acid diethyl ester are added in succession to3.88 g of3-tert-butoxycarbonyl-5(S)-[2(S)-carboxy-3-methyl-butyl]-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-2,3-oxazolidinein 190 ml of dimethylformamide at 0° C. The reaction mixture is stirredat room temperature for a further 18 hours. The reaction mixture isconcentrated by evaporation and the residue is partitioned betweendiethyl ether and saturated sodium hydrogen carbonate solution. Theorganic phases are washed with saturated sodium chloride solution andconcentrated by evaporation. The residue is purified by FC (230 g ofsilica gel, dichloromethane/methanol=95:5). The title compound isobtained: R_(f) (dichloromethane/methanol=95:5)=0.25.

c)3-Tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

53 g of3-tert-butoxycarbonyl-5(S)-(2(S)-formyl-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidineare dissolved in 470 ml of toluene, and, at 0° C., 470 ml of water, 79.1g of potassium permanganate and 9.7 g of tetrabutylammonium bromide areadded in succession thereto. The reaction mixture is stirred for afurther 48 hours at 0°-5° C., and then, at 10° C., 1.2 liters of 10%sodium sulfite solution are added. After a further 30 minutes, 1.95liters of 10% citric acid solution and 1.2 liters of water are added.The product is extracted by repeated extraction with ethyl acetate. Theextracts are concentrated by evaporation and purified by FC (2.3 kg ofsilica gel, ethyl acetate/hexane=3:7). The title compound is obtained:R_(f) (ethyl acetate/hexane=1:2)=0.21.

d)3-Tert-butoxycarbonyl-5(S)-(2(S)-formyl-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

100 g of molecular sieve (0.3 nm) and 16.6 g ofN-methylmorpholine-N-oxide are added to 53 g of3-tert-butoxycarbonyl-5(S)-(3-hydroxy-2(S)-isopropyl-propyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidinein 1.8 liters of dichloromethane at room temperature. The reactionmixture is stirred for 10 minutes and then 1.60 g of tetrapropylammoniumperrutherate are added. The reaction mixture is stirred for a further 30minutes and then filtered. The filtrate is diluted with dichloromethaneand then washed in succession with 2M sodium sulfite solution, saturatedsodium chloride solution and 1M copper(II) sulfate. The organic phase isconcentrated by evaporation and the crude title compound is obtained:R_(f) (ethyl acetate/hexane=1:2)=0.43.

e)3-Tert-butoxycarbonyl-5(S)-(3-hydroxy-2(S)-isopropyl-propyl)-4(S)-2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

3.7 g of3-tert-butoxycarbonyl-5(S)-(3-benzyloxy-2(S)-isopropyl-propyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidineare hydrogenated in the presence of 1.0 g of 5% Pd/C in 50 ml oftetrahydrofuran for 15 minutes at room temperature and under normalpressure. The reaction mixture is filtered and concentrated byevaporation. The residue is purified by means of FC (140 g of silicagel, ethyl acetate/hexane=1:2). The title compound is obtained: R_(f)(ethyl acetate/hexane=1:2)=0.28.

f)3-Tert-butoxycarbonyl-5(S)-(3-benzyloxy-2(S)-isopropyl-propyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(A)

and

3-tert-butoxycarbonyl-5(R)-(3-benzyloxy-2(S)-isopropyl-propyl-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(B)

10.9 ml of 2,2-dimethoxypropane and 10 mg of p-toluenesulfonic acid(monohydrate) are added to 7.0 g of5(S)-tert-butoxycarbonylamino-4(R,S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octyl-benzylether in 1.86 liters of dichloromethane at room temperature. Thereaction mixture is stirred at room temperature for a further 24 hours.After concentration by evaporation, the residue is purified by FC (1 kgof silica gel and dichloromethane/diethyl ether=96:4). The titlecompounds are obtained:

A) R_(f) (dichloromethane/tert-butyl methyl ether)=0.36

B) R_(f) (dichloromethane/tert-butyl methyl ether)=0.44

g)5(S)-Tert-butoxycarbonylamino-4(R,S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octyl-benzylether

51.1 g of magnesium chips are placed in 1.4 liters of tetrahydrofuran at55° C. A solution of 380 g of 2(S)-bromomethyl-3-methyl-butyl-benzylether, 30.2 ml of 1,2-dibromoethane in 0.8 liter of tetrahydrofuran at55° C. is added dropwise over a period of 30 minutes. The reactionmixture is stirred for a further 20 minutes at 55° C. and then cooled to5° C. A solution of 190 g of2(S)-tert-butoxycarbonylamino-4(S)-isopropyl-5-[4-methoxy-3-(3-methyoxypropyloxy)-phenyl]-pentanalin 0.7 liter of tetrahydrofuran is then added dropwise. The reactionmixture is stirred for a further 3 hours at room temperature, and then,at 5° C., saturated ammonium chloride solution is added and extractionis carried out with diethyl ether. The extracts are concentrated byevaporation and purified by FC (4 kg of silica gel, ethylacetate/hexane=1:3). The title compound is obtained in the form of adiastereoisomeric mixture: R_(f) (ethyl acetate/hexane=1:2)=0.26; HPLCR_(t) =22.67 and 22.81 (40:60).

h)2(S)-Tert-butoxycarbonylamino-4(S)-isopropyl-5-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-pentanal

The title compound is prepared analogously to Example 1 c) to 1 g),except that in step 1 g) instead of2(S)-isopropyl-3-(p-tert-butyl-phenyl)-propanol there is used2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propanol.That compound is prepared as follows:

i) 2(R)-Isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propanol

186 g of2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionicacid in 0.5 liter of tetrahydrofuran are added dropwise at roomtemperature to a stirred mixture of 27.2 g of sodium borohydride in 1.5liters of tetrahydrofuran. After 45 minutes a solution of 76.2 g ofiodine in 1 liter of tetrahydrofuran is added dropwise. The reactionmixture is stirred for 4 days and then 1 liter of methanol is carefullyadded dropwise. After evaporation of the solvent the residue is taken upin 2 liters of 2N hydrochloric acid and extracted repeatedly with ethylacetate. The organic extracts are washed in succession with water,saturated sodium thiosulfate solution, water/saturated sodium chloridesolution (1:1), 0.1N sodium hydroxide solution and saturated sodiumchloride solution. The organic extracts are concentrated by evaporationand purified by FC (2.4 kg of silica gel, ethyl acetate/hexane=1:4). Thetitle compound is obtained: R_(f) (ethyl acetate/hexane=1:1)=0.28.

k) 2(R)-Isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionicacid

0.434 liter of 30% hydrogen peroxide is slowly added to 300 g of4(R)-benzyl-3-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionyl}-oxazolidin-2-onein 4.8 liters of tetrahydrofuran/water (3:1) at 0° C. After the additionof 31.2 g of lithium hydroxide, the mixture is stirred for 3 hours at0°-20° C. 2.55 liters of 1.5M sodium sulfite solution are then added tothe reaction mixture at 0°-15° C. and stirring is continued for afurther 30 minutes. 1 liter of saturated sodium hydrogen carbonatesolution is added and the tetrahydrofuran is evaporated off. The aqueoussolution is washed repeatedly with dichloromethane and then acidifiedwith 2N hydrochloric acid (pH 3.0). Extraction with dichloromethane andsubsequent evaporation of the solvent yield the title compound: R_(f)(ethyl acetate/hexane=2:1)=0.30; m.p. 43.5°-44° C.

l)4(R)-Benzyl-3-{2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionyl}-oxazolidin-2-one

600 ml of tetrahydrofuran are added to a solution of 600 ml of 1Mlithium hexamethyl-disilazide and the mixture is stirred at -70° C. Thena solution of 156.6 g of 4(R)-benzyl-3-isovaleroyl-oxazolidin-2-one in500 ml of tetrahydrofuran is added dropwise and the reaction mixture isstirred for a further 75 minutes at -70° C. Then a solution of 145 g of4-methoxy-3-(3-methoxypropyloxy)-benzyl bromide in 500 ml oftetrahydrofuran is added dropwise. The temperature of the reactionmixture is allowed to rise from -70° to 0° C. over a period of 2 hours.The reaction mixture is left to stand for a further 18 hours at 4° C.and then, with stirring, 250 ml of saturated ammonium chloride solutionare added. The tetrahydrofuran is evaporated off and the residue isextracted with ethyl acetate. The title compound is obtained from theresidue of the extracts by purification by means of FC (2.4 kg of silicagel, ethyl acetate/hexane=1:1): R_(f) (ethyl acetate/hexane=1:2)=0.30;m.p. 55°-56° C.

m) 4-Methoxy-3-(3-methoxypropyloxy)-benzyl bromide

97 ml of trimethylbromosilane are added, with stirring at roomtemperature, to 113.1 g of 4-methoxy-3-(3-methoxypropyloxy)-benzylalcohol in 1.31 liters of chloroform. After 10 minutes the solvent isevaporated off and the residue is immediately purified by means of FC(900 g of silica gel, eluant: ethyl acetate/hexane 1:3). The titlecompound is obtained: R_(f) (ethyl acetate/hexane=1:2)=0.34; m.p. 50°-51° C.

n) 4-Methoxy-3-(3-methoxypropyloxy)-benzyl alcohol

7.7 g of 3-hydroxy-4-methoxy-benzyl alcohol, 10.35 g of potassiumcarbonate and 12.1 g of 1-bromo-3-methoxy-propane are stirred underreflux in 150 ml of acetone for 3 days. After evaporation of thesolvent, water is added to the residue and extraction is carried outwith ethyl acetate. After evaporation of the solvent the title compoundis obtained from the organic extracts by means of FC (240 g of silicagel, dichloromethane/methanol=96:4): R_(f) (ethylacetate/hexane=2:1)=0.31.

EXAMPLE 1255(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-morpholinopropyl)amide dihydrochloride

Analogously to Example 124, the title compound is obtained starting from120 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(3-morpholinopropyl)amide: R_(f) (dichloromethane/methanol/cone.ammonia=350:50:1)=0.12; HPLC R_(t) =9.64 minutes; FAB-MS (M+H)⁺ =580.

The starting material is prepared analogously to Example 124 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-(3-aminopropyl)morpholine.

EXAMPLE 1265(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2,2-dimethyl-2-morpholino-ethyl)amide dihydrochloride

Analogously to Example 124, the title compound is obtained starting from110 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(2,2-dimethyl-2-morpholino-ethyl)amide: R_(f)(dichloromethane/methanol=9:1)=0.05; HPLC R_(t) =10.35 minutes; FAB-MS(M+H)⁺ =594.

The starting material is prepared analogously to Example 124 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c ) and 4-(2-amino-1,1-dimethyl-ethyl)-morpholine.

a) 4-(2-Amino-1,1-dimethyl-ethyl)-morpholine

A solution of 8.33 g of 2-methyl-2-morpholino-propionic acid amide in 50ml of tetrahydrofuran is slowly added at room temperature to 3.33 g oflithium aluminium hydride in 85 ml of tetrahydrofuran. The reactionmixture is then stirred for a further 2 hours under reflux. The reactionmixture is cooled and then 5 ml of water, 6.67 ml of 2N sodium hydroxideand a further 5 ml of water are added in succession. The suspension isclarified by filtration and the crude title compound is obtained fromthe concentrated filtrate: ¹ H NMR (CDCl₃), δ(ppm)=3.67 (4H, m),2.52(2H, s), 2.48 (4H, m), 1.37 (2H, bs), 0.92 (6H, s).

b) 2-Methyl-2-morpholino-propionic acid amide

272 ml of concentrated sulfuric acid are slowly added, with stirring, to57.9 g of 2-methyl-2-morpholino-propionitrile (exothermic reaction).After the addition of 43 ml of water, the mixture is stirred for 2 hoursat 100°-110° C. The reaction mixture is cooled to 50° C. and addeddropwise at 0° C. to a solution of 846 ml of 20% ammonia in 242 ml ofwater. The mixture is then extracted repeatedly with dichloromethane.The organic phases are washed with saturated sodium chloride solutionand with sodium sulfate. The crude title compound is obtained from theconcentrated filtrate: 1H NMR (CDCl₃), δ(ppm)=7.08 (1H, bs), 5.38 (1H,bs), 3.72(4H, m), 2.53 (4H, m), 1.22(6H, s)

EXAMPLE 1275(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-thiomorpholinoethyl)amide dihydrochloride

Analogously to Example 124, the title compound is obtained starting from110 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(2-thiomorpholinoethyl)amide: R_(f)(dichloromethane/methanol=8:2)=0.33; HPLC R_(t) =10.39 minutes; FAB-MS(M+H)⁺ =582.

The starting material is prepared analogously to Example 124 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-(2-aminoethyl)thiomorpholine.

EXAMPLE 1285(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(1,1-dimethyl-2-morpholino-ethyl)amide dihydrochloride

Analogously to Example 124, the title compound is obtained staging from95 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(1,1-dimethyl-2-morpholino-ethyl)amide: R_(f)(dichloromethane/methanol=8:2)=0.42; HPLC R_(t) =10.37 minutes; FAB-MS(M+H)⁺ =594.

The starting material is prepared analogously to Example 124 a) and 130b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-(2-amino-2,2-dimethyl-ethyl)-morpholine.

EXAMPLE 1295(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(R,S)-methyl-2-morpholino-ethyl]amide dihydrochloride

Analogously to Example 124, the title compound is obtained starting from73 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[1(R,S)-methyl-2-morpholino-ethyl]amide: R_(f)(dichloromethane/methanol=8:2)=0.43; HPLC R_(t) =9.98/10.58 minutes;FAB-MS (M+H)⁺ =580.

The starting material is prepared analogously to Example 124 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-(2-amino-2(R,S)-methyl-ethyl)-morpholine.

EXAMPLE 1305(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1-carbamoyl-1-methyl-ethyl)]-amide hydrochloride

1.5 ml of trifluoroacetic acid are added to 56 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1-carbamoyl-1-methyl-ethyl)]-amide in 1.5 ml of dichloromethaneat 0° C. The mixture is stirred for a further 30 minutes at 0° C. Thereaction mixture is poured onto cooled 1N sodium hydroxide and theproduct is extracted repeatedly with dichloromethane. The organic phasesare dried, and ethereal hydrochloric acid is added. Concentration byevaporation yields the title compound: R_(f)(dichloromethane/methanol=8:2)=0.30; HPLC R_(t) =11.25; FAB-MS (M+H)⁺=538.

The starting materials are prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1-carbamoyl-1-methyl-ethyl)]-amide

5 mg of p-toluenesulfonic acid (monohydrate) are added to 82 mg of3-tert-butoxycarbonyl-5(S)-{2-[N-(1-carbamoyl-1-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidinein 5 ml of methanol at 0° C. The reaction solution is stirred for afurther 18 hours at room temperature. After evaporation of the solvent,20 ml of saturated sodium hydrogen carbonate solution are added to theresidue and extraction is carried out repeatedly with ethyl acetate. Theorganic extracts are concentrated by evaporation and purified by meansof FC (35 g of silica gel, dichloromethane/methanol=9:1). The titlecompound is obtained: R_(f) (dichloromethane/methanol=9:1)=0.47.

b)3-Tert-butoxycarbonyl-5(S)-{2-[N-(1-carbamoyl-1-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

106 μl of 4-methyl-morpholine, 66 mg of 2-aminoisobutyric acid amidehydrochloride and 91 mg ofO-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate(HBTU) are added in succession to 119 mg of3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124c) in 8 ml of dimethylformamide. The reaction mixture isstirred for 8 days at 40° C. The mixture is concentrated by evaporationand the residue is partitioned between ethyl acetate and saturatedsodium chloride solution. The organic phases are concentrated byevaporation and the residue is purified by means of FC (60 g of silicagel, dichloromethane/methanol=95:5). The title compound is obtained:R_(f) (dichloromethane/methanol=95:5)=0.30.

EXAMPLE 1315(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(N-methylcarbamoyl)-propyl]}-amide hydrochloride

The title compound is obtained analogously to Example 124 staffing from101 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(N-methylcarbamoyl)-propyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.32; HPLC R_(t) =10.11 minutes; FAB-MS(M+H)⁺ =552.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-amino-N-methylbutyric acid amide hydrochloride.

EXAMPLE 1325(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(N,N-dimethylcarbamoyl)-propyl]}-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from91 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[3-(N,N-dimethylcarbamoyl)-propyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.36; HPLC R_(t) =10.38 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-amino-N,N-dimethylbutyric acid amidehydrochloride.

EXAMPLE 1335(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N,N-dimethylcarbamoyl)ethyl]amide hydrochloride

The title compound is obtained analogously to Example 124 starting from87 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N,N-dimethylcarbamoyl)ethyl]-amide: R_(f)(dichloromethane/methanol=8:2)=0.38; HPLC R_(t) =10.31 minutes; FAB-MS(M+H)⁺ =552.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-N,N-dimethylpropionic acid amidehydrochloride.

EXAMPLE 1345(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1-carbamoylmethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from84 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1-carbamoylmethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.20; HPLC R_(t) =9.73 minutes; FAB-MS(M+H)⁺ =510.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and glycinamide hydrochloride.

EXAMPLE 1355(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoylethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from78 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoylethyl)amide: R_(f)(dichloromethane/methanol=8:2)=0.24; HPLC R_(t) =9.87 minutes; FAB-MS(M+H)⁺ =524.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-[2(S)-carboxy-3-methyl-butyl]-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-aminopropionic acid amide hydrochloride.

EXAMPLE 1365(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-carbamoylpropyl)amide hydrochloride

The title compound is obtained analogously to Example 124 starting from74 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-carbamoylpropyl)amide: R_(f)(dichloromethane/methanol=9:1)=0.06; HPLC R_(t) =10.27 minutes; FAB-MS(M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-aminobutyric acid amide hydrochloride.

EXAMPLE 1375(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)amide hydrochloride

The title compound is obtained analogously to Example 124 starting from94 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)amide: R_(f)(dichloromethane/methanol=8:2)=0.33; HPLC R_(t) =11.26 minutes; FAB-MS(M+H)⁺ =552.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2,2-dimethylpropionic acid amidehydrochloride.

EXAMPLE 1385(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2,2-dimethyl-2-(N-methylcarbamoyl)ethyl]amide hydrochloride

The title compound is obtained analogously to Example 124 starting from87 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2,2-dimethyl-2-(N-methylcarbamoyl)-ethyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.40; HPLC R_(t) =11.69 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2,2-dimethyl-N-methylpropionic acid amidehydrochloride.

a) 3-Amino-2,2-dimethyl-N-methylpropionic acid amide hydrochloride

Analogously to Example 121 a) from3-benzyloxycarbonylamino-2,2-dimethyl-N-methyl-propionic acid amide.

b) 3-Benzyloxycarbonylamino-2,2-dimethyl-N-methylpropionic acid amide

4.19 g of 3-benzyloxycarbonylamino-2,2-dimethylpropionic acid ethylester and 50 ml of 33% methylamine (in ethanol) are stirred for 8 daysat 60° C. in a bomb tube. The reaction mixture is concentrated byevaporation and the residue is purified by FC (220 g of silica gel,dichloromethane/methanol=95:5). The title compound is obtained: R_(f)(dichloromethane/methanol=9:1)=0.51.

c) 3-Benzyloxycarbonylamino-2,2-dimethylpropionic acid ethyl ester

31 ml of 90% chloroformic acid benzyl ester are slowly added, at 0°-5°C., to 29.04 g of 3-amino-2,2-dimethylpropionic acid ethyl ester in 500ml of ethyl acetate and 250 ml of 1M sodium hydrogen carbonate solution.The reaction mixture is stirred for 2 hours at 0°-5° C. and extractedwith ethyl acetate. The organic phases are washed with saturated sodiumchloride solution and then concentrated. The evaporation residue ispurified by FC (1 kg of silica gel; eluant: ethyl acetate/hexane=1:3).The title compound is obtained: R_(f) (ethyl acetate/hexane=1:3)=0.28.

EXAMPLE 1395(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-methylcarbamoyl)ethyl]amide hydrochloride

The title compound is obtained analogously to Example 124 starting from92 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-methylcarbamoyl)-ethyl]amide: R_(f)(dichloromethane/methanol=8:2)=0.24; HPLC R_(t) =10.40 minutes; FAB-MS(M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-N-methylpropionic acid amide hydrochloride.

EXAMPLE 1405(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-morpholino-3-oxopropyl)amide hydrochloride

The title compound is obtained analogously to Example 124 starting from99 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-morpholino-3-oxopropyl)amide: R_(f)(dichloromethane/methanol=8:2)=0.51; HPLC R_(t) =11.35 minutes; FAB-MS(M+H)⁺ =594.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-aminopropionic acid morpholide hydrochloride.

EXAMPLE 1415(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-1(R,S)-methyl-ethyl)amide hydrochloride

The title compound is obtained analogously to Example 124 starting from86 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-l(R,S)-methyl-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.24; HPLC R_(t) =10.43/11.16 minutes;FAB-MS (M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(R,S)-aminobutyric acid amide hydrochloride.

EXAMPLE 1425(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N-methylcarbamoyl)-1(R,S)-methyl-ethyl]}-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from95 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid{N-[2-(N-methylcarbamoyl)-1(R,S)-methyl-ethyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.33; HPLC R_(t) =10.78/11.45 minutes;FAB-MS (M+H)⁺ =552.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(R,S)-amino-N-methylbutyric acid amidehydrochloride.

EXAMPLE 1435(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylcarbamoyl)-1(R,S)-methyl-ethyl]}-amidehydrochloride

The title compound is obtained analogously to Example 124 starting from95 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylcarbamoyl)-1(R,S)-methyl-ethyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.39; HPLC R_(t) =11.44/12.04 minutes;FAB-MS (M+H)⁺ =566.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(R,S)-amino-N,N-dimethylbutyric acid amidehydrochloride.

EXAMPLE 1445-(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1(R)-isopropylethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from71 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1 (R)-isopropyl-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.27; HPLC R_(t) =10.64 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(S)-amino-4-methyl-pentanoic acid amidehydrochloride.

a) 3(S)-Amino-4-methylpentanoic acid amide hydrochloride is preparedanalogously to Example 121 a from3(R)-benzyloxycarbonylamino-4-methyl-pentanoic acid amide.

b) 3(S)-Benzyloxycarbonylamino-4-methylpentanoic acid amide

2.23 g of 3(S)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl esterand 50 ml of 6N ammonia (in methanol) are stirred for 6 days at 75° C.in a bomb tube. The reaction mixture is concentrated by evaporation andthe residue is crystallised from ethyl acetate. The title compound isobtained: R_(f) (dichloromethane/methanol=95:5)=0.20; m.p. 171°-172° C.

EXAMPLE 1455(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N-methylcarbamoyl)-1 (R)-isopropyl-ethyl]}-amidehydrochloride

The title compound is obtained analogously to Example 124 starting from81 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-methylcarbamoyl)-1 (R)-isopropyl-ethyl]amide: R_(f)(dichloromethane/methanol=8:2)=0.37; HPLC R_(t) =10.96 minutes; FAB-MS(M+H)⁺ =580.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(R)-amino-4-methyl-pentanoic acid N-(methyl)amidehydrochloride.

a) 3(R)-Amino-4-methylpentanoic acid N-(methyl)amide hydrochloride isprepared analogously to Example 121 a) from3(R)-benzyloxycarbonylamino-4-methyl-pentanoic acid N-(methyl)amide.

b) 3(R)-Benzyloxycarbonylamino-4-methylpentanoic acid N-(methyl)amide

2.23 g of 3(R)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl esterand 50 ml of 33% methylamine (in ethanol) are left to stand for 48 hoursat room temperature. The reaction mixture is concentrated by evaporationand the residue is crystallised from ethyl acetate. The title compoundis obtained: R_(f) (dichloromethane/methanol=95:5)=0.24; m.p. 190°-191°C.

EXAMPLE 1465(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylcarbamoyl)1(R)-isopropyl-ethyl]}-amidehydrochloride

The title compound is obtained analogously to Example 124 starting from72 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylcarbamoyl)-1 (R)-isopropyl-ethyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.45; HPLC R_(t) =11.76 minutes; FAB-MS(M+H)⁺ =594.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(R)-amino-4-methyl-pentanoic acid N,N-dimethylamidehydrochloride.

a) 3(R)-Amino-4-methylpentanoic acid N,N-dimethylamide hydrochloride isprepared analogously to Example 121 a) from3(R)-benzyloxycarbonylamino-4-methyl-pentanoic acid N,N-dimethylamide.

b) 3(R)-Benzyloxycarbonylamino-4-methylpentanoic acid N,N-dimethylamide

2.23 g of 3(R)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl esterand 50 ml of 30% dimethylamine (in methanol) are stirred for 6 days at75° C. in a bomb tube. The reaction mixture is concentrated byevaporation and the residue is purified by FC(dichloromethane/methanol=97:3). The title compound is obtained: R_(f)(dichloromethane/methanol=95:5)=0.40.

EXAMPLE 1475(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-2-hydroxy-ethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from82 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-2-hydroxy-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.16; HPLC R_(t) =10.09 minutes; FAB-MS(M+H)⁺ =540.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and L-serine amide hydrochloride.

EXAMPLE 1485(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S),2-dicarbamoyl-ethyl]-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from68 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S),2-dicarbamoyl-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.12; HPLC R_(t) =9.54 minutes; FAB-MS(M+H)⁺ =567.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and L-aspartic acid diamide hydrochloride.

EXAMPLE 1495(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S),3-dicarbamoylpropyl)]-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from83 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S),3-dicarbamoylpropyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.13; HPLC R_(t) =9.50 minutes; FAB-MS(M+H)⁺ =581.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and L-glutaric acid diamide hydrochloride.

EXAMPLE 1505(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoylpropyl)]-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from90 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoylpropyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.30; HPLC R_(t) =10.73 minutes; FAB-MS(M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-aminobutyric acid amide hydrochloride.

EXAMPLE 1515(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-2(S)-methyl-butyl)]-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from73 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-2(S)-methyl-butyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.36; HPLC R_(t) =11.59 minutes; FAB-MS(M+H)⁺ =566.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and L-isoleucine amide hydrochloride.

EXAMPLE 1525(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R,S)-carbamoyl-2(R,S)-methyl-ethyl]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from93 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R,S)-carbamoyl-2(R,S)-methyl-ethyl]-amide: R_(f)(dichloromethane/methanol=8:2)=0.28; HPLC R_(t) =10.19/10.31 minutes;FAB-MS (M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2(R,S)-methylpropionic acid amidehydrochloride.

EXAMPLE 1535(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R,S)-(N-methylcarbamoyl)-2(R,S)-methyl-ethyl]-amidehydrochloride

The title compound is obtained analogously to Example 124 starting from93 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R,S)-(N-methylcarbamoyl)-2(R,S)-methyl-ethyl]amide: R_(f)(dichloromethane/methanol=8:2)=0.31; HPLC R_(t) =10.76/10.85 minutes;FAB-MS (M+H)⁺ =552.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2(R,S)-methylpropionic acid N-methylamidehydrochloride.

a) 3-Amino-2(R,S)-methylpropionic acid N-methylamide hydrochloride isprepared analogously to Example 121 a) from3-benzyloxycarbonylamino-2(R,S)-methylpropionic acid N-methylamide.

b) 3-Benzyloxycarbonylamino-2(R,S)-methylpropionic acid N-methylamide

2.52 g of 3-benzyloxycarbonylamino-2(R,S)-methylpropionic acid methylester and 50 ml of 33% methylamine (in ethanol) are stirred at roomtemperature for 48 hours. The reaction mixture is concentrated byevaporation and the title compound is obtained from the residue bycrystallisation from ethyl acetate: R_(f)(dichloromethane/methanol=95:5)=0.42; m.p. 128°-129° C.

c) 3-Benzyloxycarbonylamino-2(R,S)-methylpropionic acid methyl ester

22.6 g of 3-benzyloxycarbonylamino-2(R,S)-methylpropionic acid are leftto stand for 24 hours in 230 ml of methanol with a few drops ofconcentrated sulfuric acid. The reaction mixture is concentrated byevaporation and the residue is purified by FC (220 g of silica gel,dichloromethane). The title compound is obtained: R_(f)(dichloromethane/methanol=95:5)=0.60.

d) 3-Benzyloxycarbonylamino-2(R,S)-methylpropionic acid

A solution of 41.7 ml of chloroformic acid benzyl ester (9%) in tolueneis added to 25 g of 3-amino-2(R,S)-methylpropionic acid in 533 ml of 1Nsodium hydroxide at 0° C. The reaction mixture is then stirred for 30minutes at 0° C. After the addition of 400 ml of diethyl ether, theaqueous phase is removed and 140 ml of 4N hydrochloric acid are added.The crude title compound is obtained from the organic phase byextraction with diethyl ether: R_(f)(dichloromethane/methanol=8:2)=0.41.

EXAMPLE 1545(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1(S)-methyl-ethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from445 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1(S)-methyl-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.24; HPLC R_(t) =10.27 minutes; FAB-MS(M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(S)-aminobutyric acid amide hydrochloride.

EXAMPLE 1555(S)-Amino-4(S)-hydroxy-2(S),7(S)-.diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1 (R)-methyl-ethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from110 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1(R)-methyl-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.24; HPLC R_(t) =10.92 minutes; FAB-MS(M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3(R)-aminobutyric acid amide hydrochloride.

EXAMPLE 1565(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(S)-carbamoyl-2(S)-methyl-ethyl]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from350 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(S)-carbamoyl-2(S)-methyl-ethyl]-amide (diastereoisomer A):R_(f) (dichloromethane/methanol=8:2)=0.19; HPLC R_(t) =10.50 minutes;FAB-MS (M+H)⁺ =538.

The starting material is prepared as follows:

5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(S)-carbamoyl-2(S)-methyl-ethyl]-amide (diastereoisomer A) and

5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-4-methoxy-3(3-methoxypropyloxy)-phenyl]-octanoicacid [N-[2(S)-carbamoyl-2(R)-methyl-ethyl]-amide (diastereoisomer B)

40 mg of p-toluenesulfonic acid (monohydrate) are added to 1.29 g of3-tert-butoxy-carbonyl-5(S)-{2-[N-(2-carbamoyl-2(R,S)-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidinein 50 ml of methanol at 0° C. The reaction solution is stirred for 18hours at room temperature. After removal of the solvent by evaporation,100 ml of saturated sodium hydrogen carbonate solution are added to theresidue and extraction is carried out repeatedly with ethyl acetate. Theorganic extracts are concentrated by evaporation and purified by FC (5times with 60 g of silica gel, dichloromethane/methanol=9:1). The titlecompounds are obtained:

Diastereoisomer A: R_(t) (dichloromethane/methanol=95:5)=0.19.

Diastereoisomer B: R_(t) (dichloromethane/methanol=95:5)=0.14.

The starting material is prepared analogously to Example 124 b) from3-tert-butoxy-carbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2(R,S)-methylpropionic acid amidehydrochloride.

EXAMPLE 1575(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R)-carbamoyl-2(R)-methyl-ethyl]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from370 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R)-carbamoyl-2(R)-methyl-ethyl]-amide diastereoisomer B(Example 156 a)): R_(t) (dichloromethane/methanol=8:2)=0.19; HPLC R_(t)=10.39 minutes; FAB-MS (M+H)⁺ =538.

EXAMPLE 1585(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2(R)-(N-methylcarbamoyl)-2(R)-methyl-ethyl]}-amidehydrochloride

The title compound is obtained analogously to Example 124 starting from60 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R)-(N-methylcarbamoyl)-2(R)-methyl-ethyl]-amide: R_(f)(dichloromethane/methanol=8:2)=0.31; HPLC R_(t) =10.33 minutes; FAB-MS(M+H)⁺ =552.

The starting material is prepared analogously to Example 130 a) from3-tert-butoxy-carbonyl-5(S)-{2-[N-(2(R)-(N-methylcarbamoyl)-2(R)-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine.

a)3-Tert-butoxycarbonyl-5(S)-{2(S)-[N-(2(R)-(N-methylcarbamoyl)-2(R)-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

120 mg of3-tert-butoxycarbonyl-5(S)-{2(S)-[N-(2(R)-methoxycarbonyl)-2(R)-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidineare left to stand for 48 hours at room temperature in 5 ml of 33%methylamine solution (in ethanol). The reaction mixture is concentratedby evaporation and the residue is purified by FC (30 g of silica gel,dichloromethane/methanol=95:5). The title compound is obtained: R_(f)(dichloromethane/methanol=95:5)=0.30.

b)3-Tert-butoxycarbonyl-5(S)-{2(S)-[N-(2(R)-methoxycarbonyl)-2(R)-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-propyl-2,2-dimethyl-1,3-oxazolidine

The title compound is prepared analogously to Example 124 b) from3-tert-butoxy-carbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2(R)-methylpropionic acid methyl esterhydrochloride.

c) 3-Amino-2(R)-methylpropionic acid methyl ester hydrochloride

2.7 g of 3-azido-2(R)-methylpropionic acid methyl ester are hydrogenatedin the presence of 1.4 g of 10% Pd/C in 50 ml of tetrahydrofuran for 4hours at room temperature at pH 6.0 (pH-stat; 2N hydrochloric acid). Thereaction mixture is filtered and concentrated by evaporation. The titlecompound is obtained by crystallisation from isopropanol/diethyl ether:¹ H NMR (DMSO-d₆), δ(ppm)=7.95(3H, bs), 3.65(3H, s), 3.12-2.78 (3H, m),1.15 (3H, d); m.p. 122°-125° C.

EXAMPLE 1595(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2(S)-(N-methylcarbamoyl )-2(S)-methyl-ethyl]}-amidehydrochloride

The title compound is obtained analogously to Example 124 starting from81 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid{N-[2(S)-(N-methylcarbamoyl)-2(S)-methyl-ethyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.31;HPLC R_(t) =10.50 minutes; FAB-MS(M+H)⁺ =552.

The starting material is prepared analogously to Example 158 a) to c)from3-tert-butoxy-carbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2(S)-methylpropionic acid methyl esterhydrochloride.

EXAMPLE 1605(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carboxy-2,2-dimethyl-ethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from71 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carboxy-2,2-dimethyl-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.52; HPLC R_(t) =10.95 minutes; FAB-MS(M+H)⁺ =553.

The starting material is prepared analogously to Example 130 a) from3-tert-butoxy-carbonyl-5(S)-{2(S)-[N-(2-carboxy-2,2-dimethyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine.

a)3-Tert-butoxycarbonyl-5(S)-{2(S)-[N-(2-carboxy-2,2-dimethyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

36 mg of3-tert-butoxycarbonyl-5(S)-{2(S)-[N-(2-ethyloxycarbonyl-2,2-dimethyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidineare stirred for 24 hours at room temperature in 1 ml of ethanol and 0.1ml of 2N potassium hydroxide. The reaction mixture is concentrated byevaporation and, after the addition of 0.1 ml of 2N hydrochloric acid,extracted repeatedly with diethyl ether. The extracts are concentratedby evaporation and purified by FC (18 g of silica gel,dichloromethane/methanol=9:1). The title compound is obtained: R_(f)(dichloromethane/methanol=9:1)=0.45.

The starting material is prepared analogously to Example 124 b) from3-tert-butoxy-carbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2,2-dimethylpropionic acid ethyl ester.

EXAMPLE 1615(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carboxy-2,2-diethyl-ethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from136 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(2-carboxy-2,2-diethyl-ethyl)]-amide: R_(f)(dichloromethane/methanol=8:2)=0.26; HPLC R_(t) =12.53 minutes; FAB-MS(M+H)⁺ =581.

The starting material is prepared analogously to Example 130 a) from3-tert-butoxy-carbonyl-5(S)-{2(S)-[N-(2-carboxy-2,2-diethyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine.

a)3-Tert-butoxycarbonyl-5(S)-{2-N-(2-carboxy-2,2-diethyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine

258 mg of3-tert-butoxycarbonyl-5(S)-{2-[N-(2-(2-ethyloxycarbonyl-2,2-diethyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidineare stirred for 24 hours at 80° C. in 6 ml of ethanol and 0.69 ml of 2Npotassium hydroxide. The reaction mixture is concentrated by evaporationand, after the addition of 0.69 ml of 2N hydrochloric acid, extractedrepeatedly with diethyl ether. The extracts are concentrated byevaporation and purified by FC (35 g of silica gel,dichloromethane/methanol=9:1). The title compound is obtained: R_(f)(dichloromethane/methanol=9:1)=0.50.

The starting material is prepared analogously to Example 124 b) from3-tert-butoxy-carbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 3-amino-2,2-diethylpropionic acid ethyl ester.

EXAMPLE 1625(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[(1-carboxy-cyclopentyl)-methyl]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from142 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7 (S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acidN-[(1-carboxy-cyclopentyl)-methyl]-amide: R_(f)(dichloromethane/methanol=8:2)=0.26; HPLC R_(t) =12.18 minutes; FAB-MS(M+H)⁺ =579.

The starting material is prepared analogously to Examples 130 a), 161 a)and 124 b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 1-(aminomethyl)cyclopentane-1-carboxylic acid ethylester.

EXAMPLE 1635(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(1H-tetrazol-5-yl)-ethyl]}-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from100 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(1H-tetrazol-5-yl)-ethyl]}-amide: R_(f)(dichloromethane/methanol=8:2)=0.19; HPLC R_(t) =12.30 minutes; FAB-MS(M+H)⁺ =549.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2-(1H-tetrazol-5-yl)-ethylamine.

EXAMPLE 1645(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-(5-oxopyrrolidin-2-yl)methyl]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from100 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[(1-carboxy-cyclopentyl)-methyl]-amide: R_(f)(dichloromethane/methanol=8:2)=0.27; HPLC R_(t) =12.55 minutes; FAB-MS(M+H)⁺ =550.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 5(S)-(aminomethyl)-2-pyrrolidone.

EXAMPLE 1655(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1 (R)-(5-oxopyrrolidin-2-yl)methyl]-amide hydrochloride

The title compound is obtained analogously to Example 124 starting from95 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1 (R)-(5-oxopyrrolidin-2-yl)methyl]-amide: R_(f)(dichloromethane/methanol=8:2)=0.31; HPLC R_(t) =12.24 minutes; FAB-MS(M+H)⁺ =550.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 5(R)-(aminomethyl)-2-pyrrolidone.

EXAMPLE 1665(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[(N,N-dimethyl)-carbamoylmethyl]}-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from56 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[(N,N-dimethyl)-carbamoylmethyl]}-amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/conc. ammonia=80:15:5)=0.42; HPLC R_(t) =11.82 minutes; FAB-MS (M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-aminoacetic acid (N,N-dimethyl)-amidehydrochloride.

EXAMPLE 1675(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[N-(morpholin-4-yl)carbamoylmethyl]amide hydrochloride

The title compound is obtained analogously to Example 130 starting from76 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[N-(morpholin-4-yl)carbamoylmethyl]-amide and afterlyophilisation: R_(t) (ethyl acetate/methanol/conc.ammonia=80:15:5)=0.43; HPLC R_(t) =10.66 minutes; FAB-MS (M+H)⁺ =580.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2-aminoacetic acid N-(morpholin-4-yl)amidehydrochloride.

EXAMPLE 1685(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-ethyl)]-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from64 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoylethyl)]-amide and after lyophilisation: R_(f)(ethyl acetate/methanol/conc. ammonia=80: 15:5)=0.42; HPLC R_(t) =10.48minutes; FAB-MS (M+H)⁺ =524.

The starting material is prepared analogously to Examples 130 a) and 130b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-aminopropionic acid amide hydrochloride.

EXAMPLE 1695(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{1(S)-[(N-methyl)-carbamoyl]-ethyl}-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from31 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{1(S)-[(N-methyl)-carbamoyl]-ethyl}-amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/conc.ammonia=80:15:5)=0.38; HPLC R_(t) =11.08 minutes; FAB-MS (M+H)⁺ =538.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-aminopropionic acid (N-methyl)-amidehydrochloride.

EXAMPLE 1705(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{1(S)-[(N,N-dimethyl)-carbamoyl]-ethyl}-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from86 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{1(S)-[(N,N-dimethyl)-carbamoyl]-ethyl}-amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/conc.ammonia=80:15:5)=0.50; HPLC R_(t) =11.53 minutes; FAB-MS (M+H)⁺ =552.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-aminopropionic acid (N,N-dimethyl)-amidehydrochloride.

EXAMPLE 1715(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{1(S)-N-[(morpholin-4-yl)-carbamoyl]-ethyl}amide hydrochloride

The title compound is obtained analogously to Example 130 starting from51 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{1(S)-N-[(morpholin-4-yl)-carbamoyl]-ethyl}amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/conc.ammonia=80:15:5)=0.51; HPLC R_(t) =11.29 minutes; FAB-MS (M+H)⁺ =594.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-aminopropionic acid N-(morpholin-4-yl)amidehydrochloride.

EXAMPLE 1725(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-carbamoyl-butyl]amide hydrochloride

The title compound is obtained analogously to Example 130 starting from49 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-carbamoylbutyl]amide and after lyophilisation: R_(t) (ethylacetate)=0.38; HPLC R_(t) =10.67 minutes; FAB-MS (M+H)⁺ =552.

The starting material is prepared analogously to Example 130 a) and 130b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-aminopentanoic acid amide hydrochloride.

EXAMPLE 1735(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-carbamoyl-2-methyl-propyl]-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from65 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-carbamoyl-2-methyl-propyl]-amide and after lyophilisation:R_(f) (ethyl acetate/methanol/conc. ammonia=80: 15:5)=0.47; HPLC R_(t)=11.22 minutes; FAB-MS (M+H)⁺ =552.

The starting material is prepared analogously to Example 130 a) and 130b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-amino-3-methylbutyric acid amide hydrochloride.

EXAMPLE 174 5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy,.3-(3-methoxypropyloxy)-phenyl]-octanoic acid N-[1(S):(N-methylcarbamoyl)-2-methyl-propyl]amide hydrochloride

The title compound is obtained analogously to Example 130 starting from58 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-(N-methylcarbamoyl)-2-methyl-propyl]amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/conc.ammonia=80:15:5)=0.51; HPLC R_(t) =11.87 minutes; FAB-MS (M+H)⁺ =566.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-amino-3-methylbutyric acid (N-methyl)amidehydrochloride.

EXAMPLE 1755(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-(N,N-dimethylcarbamoyl)-2-methyl-propyl]amide hydrochloride

The title compound is obtained analogously to Example 130 starting from80 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[1(S)-(N,N-dimethylcarbamoyl)-2-methyl-propyl]amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/conc.ammonia=80:15:5)=0.62; HPLC R_(t) =12.36 minutes; FAB-MS (M+H)⁺ =580.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-amino-3-methylbutyric acid (N,N-dimethyl)amidehydrochloride.

The starting material is prepared as follows:

a) 2(S)-Amino-3-methylbutyric acid (N,N-dimethyl)amide hydrochloride

0.85 g of 2(S)-tert-butoxycarbonylamino-3-methylbutanoic acid(N,N-dimethyl)amide is dissolved in 10 ml of 4N hydrochloric acid indioxane at 0° C. and stirred for 7 hours at 0° C. The reaction mixtureis lyophilised and the title compound is obtained: R_(f) (ethylacetate/methanol/conc. ammonia=80:15:5)=0.23.

EXAMPLE 176 5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-.3-(3-methoxypropyloxy)-phenyl]-octanoic acidN-{1(S)-[N-(morpholin-4-yl)carbamoyl]-2-methyl-propyl}amidehydrochloride

The title compound is obtained analogously to Example 130 starting from74 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{1(S)-[N-(morpholin-4-yl)carbamoyl]-2-methyl-propyl}amide andafter lyophilisation: R_(f) (ethyl acetate/methanol/conc.ammonia=80:15:5)=0.59; HPLC R_(t) =11.81 minutes; FAB-MS (M+H)⁺ =622.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2(S)-amino-3-methylbutanoic acidN-(morpholin-4-yl)amide hydrochloride.

EXAMPLE 1775(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-methylsulfonyl)ethyl]amide hydrochloride

The title compound is obtained analogously to Example 124 starting from90 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-methylsulfonyl)ethyl]amide and after lyophilisation: R_(f)(ethyl acetate/methanol/conc. ammonia=80:15:5)=0.52; HPLC R_(t) =11.50minutes; FAB-MS (M+H)⁺ =574.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2-aminoethyl-(N-methyl)-sulfonamide.

EXAMPLE 1785(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{2-[N-(morpholin-4-yl)-sulfonyl]ethyl}-amide hydrochloride

The title compound is obtained analogously to Example 130 starting from98 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-{2-[N-(morpholin-4-yl)-sulfonyl]ethyl}-amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/conc. ammonia=80:15:5)=0.53; HPLC R_(t) =11.63 minutes; FAB-MS (M+H)⁺ =630.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 2-aminoethyl-N-(morpholin-4-yl)-sulfonamide.

The starting material is prepared as follows:

a) 2-Aminoethyl-N-(morpholin-4-yl)-sulfonamide

3.0 g of 2-phthaloylaminoethyl-N-(morpholin-4-yl)-sulfonamide in 20 mlof methanol are stirred for 2 hours under reflux with 20 ml of hydrazinehydrate. The reaction mixture is cooled and 1.0 ml of concentratedhydrochloric acid and 15 ml of methanol are added. The reaction mixtureis filtered and the filtrate is concentrated. After the addition of 10ml of 10% potassium hydroxide solution the title compound is obtained byextraction with dichloromethane: R_(f) (ethyl acetate/methanol/cone.ammonia=80:15:5)=0.26.

b) 2-Phthaloylaminoethyl-N-(morpholin-4-yl)-sulfonamide

4.77 ml of morpholine are added to 5.0 g of2-phthaloylaminoethylsulfonyl chloride in 40 ml of dichloromethane at-12° C. The reaction mixture is stirred for 30 minutes at 0° and washedwith water. The organic phase is dried over sodium sulfate andconcentrated. The title compound is obtained: R_(f) (ethylacetate/methanol/cone. ammonia=80:15:5)=0.68.

EXAMPLE 1795(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-.[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-acetyl)-piperidin-4-yl)ethyl]amide hydrochloride

The title compound is obtained analogously to Example 124 starting from42 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-acetyl)-piperidin-4-yl)ethyl]amide and afterlyophilisation: R_(f) (ethyl acetate/methanol/cone.ammonia=80:15:5)=0.51; HPLC R_(t) =12.06 minutes; FAB-MS (M+H)⁺ =606.

The starting material is prepared analogously to Examples 130 a) and 124b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-(2-aminoethyl)-(N-acetyl)-piperidinehydrochloride.

The starting material is prepared as follows:

a) 4-(2-Aminoethyl)-(N-acetyl)-piperidine hydrochloride is preparedanalogously to Example 175 a) from4-(2-tert-butoxycarbonylaminoethyl)-(N-acetyl)-piperidine.

b) N-Acetyl-4-(2-tert-butoxycarbonylaminoethyl)-piperidine

0.5 g of 4-(2-tert-butoxycarbonylaminoethyl)-piperidine and 0.61 ml oftriethylamine are dissolved in 5 ml of dichloromethane and, at 0° C.,0.22 ml of acetyl chloride is added. The reaction mixture is stirred atroom temperature for 7 hours and then washed with water. The organicphase is concentrated by evaporation and purified by FC (10 g of silicagel, ethyl acetate/methanol=9:1). The title compound is obtained: R_(e)(ethyl acetate/methanol=9:1)=0.39.

EXAMPLE 1805(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[(N-acetyl-piperidin-4-yl)methyl]amide hydrochloride

The title compound is obtained analogously to Example 130 starting from71 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[(N-acetylpiperidin-4-yl)methyl]amide and after lyophilisation:R_(t) (ethyl acetate/methanol/conc. ammonia=80:15:5)=0.44; HPLC R_(t)=12.83 minutes; FAB-MS (M+H)⁺ =629.

The starting material is prepared analogously to Examples 130 a) and 130b) from3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine(Example 124 c) and 4-aminomethyl-(N-acetyl)-piperidine hydrochloride.

EXAMPLE 1815(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxybutyl)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)amide hydrochloride

The title compound is obtained analogously to Example 105 starting from25 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxybutyl)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)amide: R_(f)(dichloromethane/methanol/conc. ammonia=350:50:1)=0.30; HPLC R_(t)=13.31 minutes; FAB-MS (M+H)⁺ =550.

The starting material is prepared analogously to Example 82 d), 82 e),Example 83 d), Example 83 and Example 105, except that there is usedinstead of 4-(3-benzyloxy-propyloxy)-3-(3-methoxypropyloxy)-bromobenzenein Example 82 d), 4-methoxy-3-(4-methoxy-butyl)-bromobenzene, which isprepared as follows:

a) 4-Methoxy-3-(4-methoxybutyl)-bromobenzene

A solution of 50 g of 4-methoxy-3-(4-methoxy-2-butenyl)-bromobenzene in700 ml of tetrahydrofuran is hydrogenated for 2 hours under normalpressure and at room temperature in the presence of 2.5 g of 5% Pt/C.The reaction mixture is filtered. The filtrate is concentrated byevaporation. The evaporation residue obtained from the filtrate ispurified by FC (1.6 kg of silica gel, hexane/ethyl acetate=20:1).Distillation under a high vacuum yields the title compound: R_(t)(hexane/ethyl acetate=10:1)=0.38; HPLC R_(t) =19.92 minutes; FAB-MS(M+H)⁺ =273.

b) 4-Methoxy-3-(4-methoxy-2-butenyl)-bromobenzene

25 1.1 g of 3-methoxypropyltriphenylphosphonium bromide are added to asolution, stirred at 5°, of 110.8 g of sodium bis(trimethylsilyl)amidein 1200 ml of tetrahydrofuran. The reaction mixture is further stirredfor 45 minutes at 0° and then a solution of 100 g of5-bromo-o-anisaldehyde in 1000 ml of tetrahydrofuran is added dropwisethereto. The reaction mixture is stirred for a further 1 hour at 0°.Then, at 0° C., 1 liter of a saturated ammonium chloride solution isadded dropwise. After concentration, the residue is extracted 4 timeswith ethyl acetate. The organic phases are washed with water andsaturated sodium chloride solution and concentrated by evaporation. Theresidue is purified by FC (500 g of silica gel, hexane/ethylacetate=5:1). Distillation under a high vacuum yields the titlecompound: R_(f) (hexane/ethyl acetate=4:1)=0.61.

EXAMPLE 1825(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N,N-dimethylcarbamoyl)ethyl]-amide sodium dihydrogen citrate

768 mg of5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(N,N-dimethylcarbamoyl)ethyl]amide hydrochloride (Example 134)are stirred in 50 ml of 0.1N sodium hydroxide and extracted repeatedlywith dichloromethane. The extracts are concentrated and the residue isdissolved in 50 ml of ethanol. 274 mg of citric acid monohydrate, 50 mlof water and 1.30 ml of 1N sodium hydroxide are added in succession tothe stirred solution. The solution is then concentrated to dryness byevaporation and the residue is taken up in 100 ml of water andlyophilised. The lyophilisate is dissolved in methanol and clarified byfiltration; the filtrate is concentrated and the residue is dried atroom temperature under a high vacuum. The title compound is obtained inthe form of a white amorphous solid having a melting point of 80° C.

EXAMPLE 1835(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxybutyl)-phenyl-octanoicacid N-(2-morpholinoethyl)amide dihydrochloride

The title compound is obtained analogously to Example 124 starting from100 mg of5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3(4-methoxybutyl)-phenyl]-octanoicacid N-[2-(4-morpholino)ethyl]-amide: R_(f)(dichloromethane/methanol=10:1)=0.21; HPLC R_(t) =12.69 minutes; FAB-MS(M+H)⁺ =564.

The starting material is prepared as follows:

a)5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxybutyl)-phenyl]-octanoicacid N-[2-(4-morpholino)-ethyl]-amide

10 ml of acetic acid are added to a solution of 100 mg of3(S)-isopropyl-5(S)-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(4-methoxybutyl)-phenyl]-butyl]-tetrahydrofuran-2-one(for preparation see Example 181) in 2 ml of 4-(2-aminoethyl)morpholine.The reaction mixture is stirred for 39 hours at 80° C. and thenconcentrated by evaporation in a rotary evaporator. Purification of theresidue by FC (dichloromethane/methanol=10:1) yields the title compoundin the form of a crude product. Crystallisation from diethylether/hexane yields the title compound: m.p. -94°-96° C., R_(f)(dichloromethane/methanol=10:1) -0.35; HPLC R_(t) =17.42 minutes; FAB-MS(M+H)⁺ =664.

EXAMPLE 1845(S)-Amino-4(S),8(R,S)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-.3-(2-methoxymethoxyethyl)-phenyl]-octanoic acid (N-butyl)-amide

40 mg of5(S)-azido-4(S),8(R,S)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-octanoicacid (N-butyl)-amide are hydrogenated in 10 ml of methanol/acetic acid(9:1) in the presence of 20 mg of 10% Pd/C at room temperature and undernormal pressure. The reaction mixture is filtered and concentrated byevaporation. The residue is purified by FC (2.4 g of silica gel,dichloromethane/methanol=9:1). The title compound is obtained: R_(f)(dichloromethane/methanol=9:1)=0.17; HPLC R_(t) =11.44 and 12.63 minutes(diastereoisomeric mixture); FAB-MS (M+H)+=525.

a)5(S)-Azido-4(S)-8(R,S)-dihydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxy-methoxyethyl)-phenyl]-octanoicacid (N-butyl)-amide

A solution of 400 mg of3(S)-isopropyl-5(S)-{1(S)-azido-4(R,S)-hydroxy-3(S)-isopropyl-4-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-butyl}-tetrahydrofuran-2-one (Example 81 d) and 3.8 ml ofn-butylamine is stirred for 16 hours at 50° C. and then concentrated byevaporation. Purification of the residue by FC (50 g of silica gel,hexane/ethyl acetate=1:1) yields the title compound: R_(f) (hexane/ethylacetate=1:1)=0.44; HPLC R_(t) =16.13 and 17.03 minutes(diastereoisomeric mixture).

EXAMPLE 185 5(S)-Amino-4(S),8(S orR)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide hydrochloride

60 mg of 5(S)-azido-4(S),8(S orR)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide and 6 ml of ethanolamineare hydrogenated in 8 ml of ethanol in the presence of 120 mg of 5%PdO/C for 2 hours at room temperature and under normal pressure. Thereaction mixture is filtered and concentrated by evaporation. Theresidue is dissolved in 0.5 ml of dioxane and 23 ul of 4N hydrochloricacid in dioxane are added. The title compound is obtained afterlyophilisation: HPLC R_(t) =10.74; FAB-MS (M+H)+=568.

The starting materials are prepared as follows:

a) 5(S)-Azido-4(S),8(S orR)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide

150 mg of 3(S)-isopropyl-5(S)-{1(S)-azido-4(S orR)-hydroxy-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one(Example 185b) diastereoisomer B) and 109 mg of3-amino-2,2-dimethylpropionic acid amide are stirred in 3 ml oftriethylamine with 30 mg of 2-hydroxypyridine for 24 hours under refluxtemperature. After removal of the solvent by evaporation, the residue,in diethyl ether, is washed repeatedly with water. The organic extractsare concentrated by evaporation and purified by FC (10 g of silica gel,dichloromethane/methanol=95:5). The title compound is obtained: R_(f)(dichloromethane/methanol=95:5)=0.22; HPLC R_(t) =14.88 minutes.

b) 3(S)-Isopropyl-5(S)-{1(S)-azido-4(S orR)-hydroxy-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one(A) and

3(S)-isopropyl-5(S)-{1(S)-azido-4(S orR)-hydroxy-3(S)-isopropyl-4-I4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one(B)

Separation of 0.5 g of3(S)-isopropyl-5(S)-{1(S)-azido-4(R,S)-hydroxy-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one(diastereoisomeric mixture) by means of preparative HPLC on Kromasil 7C18 (EKA-Nobel, A.B. Sweden); mobile phase: A) water B) acetonitrile,gradient: 20 -80% B in 40 minutes. The two pure diastereoisomers A and Bare obtained (isomer A is eluted first). After concentration of theeluate fractions by evaporation, the aqueous residue is extracted withethyl acetate. The organic extracts are dried over magnesium sulfate andconcentrated. The title compounds are obtained: diastereoisomer A) HPLCR_(t) =18.53 minutes and B) HPLC R_(t) =19.49 minutes.

c)3(S)-Isopropyl-5(S)-1(S)-azido-4(R,S)-hydroxy-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one

45.1 ml of a 1N n-butyllithium solution (in hexane) are added dropwiseat -75° C. to a mixture of 12.1 g of4-methoxy-3-(3-methoxypropyloxy)-bromobenzene and 9.7 ml of4-methylmorpholine in 75 ml of tetrahydrofuran. The reaction mixture isstirred for a further 20 minutes at -75° C. and then, at from -75° C. to-60° C., a suspension of magnesium bromide in tetrahydrofuran (freshlyprepared from 1.6 g of magnesium powder and 5.7 ml of 1,2-dibromoethanein 150 ml of tetrahydrofuran) is added. The reaction mixture is stirredfor a further 30 minutes and then, at -75° C., a solution of 8.84 g of3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-onein 75 ml of tetrahydrofuran is added. The reaction mixture is thenstirred for 15 minutes at -75° C. and subsequently 70 ml of saturatedammonium chloride solution are added. The reaction mixture is thenpoured into 180 ml of saturated sodium chloride solution:water (1:1) andextracted with ethyl acetate (2x360 ml). The organic phases are driedover magnesium sulfate and concentrated by evaporation. The titlecompound is obtained by purifying the residue by FC (240 g of silicagel, ethyl acetate/hexane=1:2): R_(f) (ethyl acetate/hexane=1:2)=0.16;HPLC R_(t) =18.53 and 19.49 minutes (diastereoisomeric mixture).

d) 4-Methoxy-3-(3-methoxypropyloxy)-bromobenzene

66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added atroom temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in350 ml of acetonitrile. The reaction mixture is stirred under reflux for14 hours. After removal of the solvent by evaporation, 1200 ml ofice/water are added to the residue and extraction is carried out withether. The organic extracts are washed with saturated sodium chloridesolution, dried over magnesium sulfate and concentrated by evaporation.Distillation under a high vacuum yields the title compound: R_(e)(hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC R_(t)=16.38 minutes; MS (M⁺)=274, 276.

EXAMPLE 186 5(S)-Amino-4(S),8(R orS)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide hydrochloride

The title compound is obtained analogously to Example 185 starting from5(S)-azido-4(S),8(R orS)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide: HPLC R_(t) =10.68; FAB-MS(M+H)⁺ =568.

The starting material is prepared analogously to Example 185a) from3(S)-isopropyl-5(S)-{1(S)-azido-4(R orS)-hydroxy-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one(Example 185 b) diastereoisomer A).

EXAMPLE 187 Gelatin solution

A sterile-filtered aqueous solution, containing 20% cyclodextrins assolubiliser, of one of the compounds of formula I mentioned in thepreceding Examples as active ingredient, is so mixed, with theapplication of heat and under aseptic conditions, with a sterile gelatinsolution containing phenol as preservative, that 1.0 ml of solution hasthe following composition:

    ______________________________________                                        active ingredient           3      mg                                         gelatin                     150.0  mg                                         phenol                      4.7    mg                                         dist. water containing 20% cyclodextrins as solubiliser                                                   1.0    ml                                         ______________________________________                                    

EXAMPLE 188 Sterile dry substance for injection

5 mg of one of the compounds of formula I mentioned in the precedingExamples as active ingredient are dissolved in 1 ml of an aqueoussolution containing 20 mg of mannitol and 20% cyclodextrins assolubiliser. The solution is sterile-filtered and, under asepticconditions, introduced into a 2 ml ampoule, deep-frozen and lyophilised.Before being used, the lyophilisate is dissolved in 1 ml of distilledwater or 1 ml of physiological saline. The solution is administeredintramuscularly or intravenously. The formulation can also be filledinto double-chamber disposable syringes.

EXAMPLE 189 Nasal spray

500 mg of finely ground (<5.0 gm) powder of one of the compounds offormula I mentioned in the preceding Examples are suspended as activeingredient in a mixture of 3.5 ml of "Myglyol 8 12" and 0.08 g of benzylalcohol. The suspension is introduced into a container having a meteringvalve. 5.0 g of "Freon 12" are introduced under pressure through thevalve into the container. The "Freon" is dissolved in the Myglyol/benzylalcohol mixture by shaking. The spray container contains approximately100 single doses which can be administered individually.

EXAMPLE 190 Film-coated tablets

The following constituents are processed for the preparation of 10 000tablets each containing 100 mg of active ingredient:

    ______________________________________                                        active ingredient  1000 g                                                     corn starch        680 g                                                      colloidal silicic acid                                                                           200 g                                                      magnesium stearate  20 g                                                      stearic acid        50 g                                                      sodium carboxymethyl starch                                                                      250 g                                                      water              quantum satis                                              ______________________________________                                    

A mixture of one of the compounds of formula I mentioned in thepreceding Examples as active ingredient, 50 g of corn starch and thecolloidal silicic acid is processed into a moist mass with starch pasteprepared from 250 g of corn starch and 2.2 kg of demineralised water.The mass is forced through a sieve having a mesh size of 3 mm and driedat 45° for 30 minutes in a fluidised bed drier. The dried granules arepressed through a sieve having a mesh size of 1 ram, mixed with apreviously sieved mixture (1 mm sieve) of 330 g of corn starch, themagnesium stearate, the stearic acid and the sodium carboxymethylstarch, and compressed to form slightly biconvex tablets.

What is claimed is:
 1. A novel δ-amino-γ-hydroxy-ω-aryl-alkanoic acidamide of formula I ##STR39## wherein R₁ is hydrogen, hydroxy, loweralkoxy, cycloalkoxy, lower alkoxy-lower alkoxy or free or esterified oramidated carboxy-lower alkoxy.R₂ is hydrogen, lower alkyl, cycloalkyl,lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,cycloalkoxy-lower alkyl, hydroxy, optionally lower alkanoylated,halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower alkyl thatis unsubstituted or substituted by lower alkyl, by lower alkanoyl and/orby lower alkoxycarbonyl; optionally hydrogenated heteroaryl-lower alkyl;amino-lower alkoxy that is substituted by lower alkyl, by lower alkanoyland/or by lower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy,cycloalkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, loweralkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-loweralkoxy, lower alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl,lower alkanoyl-lower alkoxy, optionally S-oxidised lower alkylthio-loweralkoxy, lower alkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy,optionally hydrogenated heteroaryl-lower alkoxy, cyano-lower alkoxy,free or esterified or amidated carboxy-lower alkoxy or free oresterified or amidated carboxy-lower alkyl. R₃ is optionally halogenatedlower alkyl, lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl,hydroxy-lower alkyl, optionally S-oxidised lower alkylthio-lower alkyl,optionally hydrogenated heteroarylthio-lower alkyl, optionallyhydrogenated heteroaryl-lower alkyl; amino-lower alkyl that isunsubstituted or N-mono- or N,N-di-lower alkylated. N-lower alkanoylatedor N-lower alkane-sulfonylated or N,N-disubstituted by lower alkylene,by unsubstituted or N'-lower alkylated or N'-lower alkanoylatedaza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidisedthia-lower alkylene; cyano-lower alkyl, free or esterified or amidatedcarboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy,cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy,hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated loweralkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally hydrogenatedheteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted orN-mono- or N,N-di-lower alkylated. N-lower alkanoylated or N-loweralkanesulfonylated or substituted by lower alkylene, by unsubstituted orN'-lower alkylated or N'-lower alkanoylated aza-lower alkylene, byoxa-lower alkylene or by optionally S-oxidised thia-lower alkylene;cyano-lower alkoxy or free or esterified or amidated carboxy-loweralkoxy, R₄ is hydrogen, lower alkyl, hydroxy, lower alkoxy orcycloalkoxy. X is methylene, R₅ is lower alkyl or cycloalkyl. R₆ isunsubstituted or N-mono- or N,N-di-lower alkylated or N-loweralkanoylated amino, R₇ is lower alkyl, lower alkenyl, cycloalkyl oraryl-lower alkyl, and R₈ is lower alkyl, cycloalkyl, free oraliphatically esterified or etherified hydroxy-lower alkyl; amino-loweralkyl that is unsubstituted or N-lower alkanoylated or N-mono- orN,N-di-lower alkylated or N,N-disubstituted by lower alkylene, byhydroxy-. lower alkoxy- or lower alkanoyloxy-lower alkylene, byunsubstituted or N'-lower alkanoylated or N'-lower alkylated aza-loweralkylene, by oxa-lower alkylene or by optionally S-oxidised thia-loweralkylene; free or esterified or amidated carboxy-lower alkyl, free oresterified or amidated dicarboxy-lower alkyl, free or esterified oramidated carboxy-(hydroxy)-lower alkyl, free or esterified or amidatedcarboxycycloalkyl-lower alkyl, cyano-lower alkyl, loweralkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-loweralkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- orN,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radicalbonded via a carbon atom and optionally hydrogenated and/oroxo-substituted, or lower alkyl substituted by a heteroaryl radicalbonded via a carbon atom and optionally hydrogenated and/oroxo-substituted,or a salt thereof.
 2. A compound according to claim 1 offormula I whereinR₁ is hydrogen, hydroxy, lower alkoxy, cycloalkoxy,lower alkoxy-lower alkoxy, carboxy-lower alkoxy, loweralkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy or N-mono- orN,N-di-lower alkylcarbamoyl-lower alkoxy. R₂ is hydrogen, lower alkyl,cycloalkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-loweralkyl, cycloalkoxy-lower alkyl, hydroxy, lower alkanoyloxy-lower alkyl,hydroxy-lower alkoxy, halo-(hydroxy)-lower alkoxy, loweralkane-sulfonyl-(hydroxy)-lower alkoxy, amino-lower alkyl, loweralkylamino-lower alkyl, di-lower alkylamino-lower alkyl, loweralkanoylamino-lower alkyl, lower alkoxycarbonylamino-lower alkyl,amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkoxycarbonylamino-lower alkoxy, oxo-lower alkoxy, lower alkoxy,cycloalkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, loweralkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-loweralkoxy, lower alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl,lower alkanoyl-lower alkoxy, lower alkylthio-lower alkoxy, loweralkanesulfonyl-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy,aryl-lower alkoxy, thiazolylthio-lower alkoxy or thiazolinylthio-loweralkoxy, imidazolylthio-lower alkoxy, optionally N-oxidisedpyridylthio-lower alkoxy, pyrimidinylthio-lower alkoxy, cyano-loweralkoxy, lower alkoxycarbonyi-lower alkoxy, carbamoyl-lower alkoxy,N-mono- or N, N-all-lower alkylcarbamoyl-lower alkoxy, carboxy-loweralkyl, lower alkoxy-carbonyl-lower alkyl, carbamoyl-lower alkyl orN-mono- or N,N-di-lower alkyl-carbamoyl-lower alkyl, R₃ is lower alkyl,polyhalo-lower alkyl, lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl,hydroxy-lower alkyl, lower alkylthio-lower alkyl, loweralkanesulfonyl-lower alkyl, optionally partially hydrogenated orN-oxidised pyridyl-lower alkyl, thiazolylthio-lower alkyl orthiazolinylthio-lower alkyl, imidazolylthio-lower alkyl, optionallyN-oxidised pyridylthio-lower alkyl, pyrimidinylthio-lower alkyl,amine-lower alkyl, lower alkylamino-lower alkyl, di-loweralkylamino-lower alkyl, lower alkanoylamino-lower alkyl, loweralkanesulfonylamino-lower alkyl, polyhalo-loweralkanesulfonylamino-lower alkyl, pyrrolidino-lower alkyl,piperidino-lower alkyl, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkyl, morpholino-lower alkyl,thiomorpholino-. S-oxothiomorpholino- or S,S-dioxothiomorpholino-loweralkyl, cyano-lower alkyl, carboxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- orN,N-di-lower alkylcarbamoyl-lower alkyl, cycloalkyl; phenyl or naphthylthat is unsubstituted or mono-. di- or tri-substituted by lower alkyl,lower alkoxy, hydroxy, lower alkylamino, di-lower alkylamino, halogenand/or by trifluoromethyl; hydroxy, lower alkoxy, cycloalkoxy, loweralkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy;phenyl-lower alkoxy or naphthyl-lower alkoxy that is unsubstituted ormono-, di- or tri-substituted by lower alkyl, lower alkoxy, hydroxy,lower alkylamino, di-lower alkylamino, halogen and/or bytrifluoromethyl; lower alkoxy, polyhalo-lower alkoxy, loweralkylthio-lower alkoxy, lower alkanesulfonyl-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally partially or fullyhydrogenated hetero-arylthio-lower alkoxy, such as thiazolylthio-loweralkoxy or thiazolinylthio-lower alkoxy, imidazolylthio-lower alkoxy,optionally N-oxidised pyridylthio-lower alkoxy, pyrimidinylthio-loweralkoxy, amine-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkanesulfonylamino-lower alkoxy, polyhalo-loweralkanesulfonylamino-lower alkoxy, pyrrolidino-lower alkoxy,piperidino-lower alkoxy, piperazino-, N'-lower alkylpiperazino- orN'-lower alkanoylpiperazino-lower alkoxy, morpholino-lower alkoxy,thiomorpholino-, S-oxothiomorpholino-or S,S-dioxothiomorpholino-loweralkoxy, cyano-lower alkoxy, carboxy-lower alkoxy, loweralkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy or N-mono- orN,N-di-lower alkylcarbamoyl-lower alkoxy, R₄ is hydrogen, lower alkyl,hydroxy, lower alkoxy or cycloalkoxy. X is methylene, R₅ is lower alkylor cycloalkyl. R₆ is amino, lower alkylamino, di-lower alkylamino orlower alkanoylamino, R₇ is lower alkyl, lower alkenyl, cycloalkyl, orphenyl- or naphthyl-lower akyl that is unsubstituted or mono-, di- ortri-substituted by lower alkyl, lower alkoxy, hydroxy, lower alkylamino,di-lower alkylamino, halogen and/or by trifluoromethyl, and R₈ is loweralkyl, cycloalkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl,lower alkoxy-lower alkyl or lower alkenyloxy-lower alkyl, amino-loweralkyl, lower alkanoylamino-lower alkyl. N-mono- or N,N-di-loweralkylamino-lower alkyl, optionally hydroxylated or lower alkoxylatedpiperidino-lower alkyl, such as piperidino-lower alkyl,hydroxypiperidino-lower alkyl or lower alkoxy-piperidino-lower alkyl,piperazino-, N'-lower alkylpiperazino- or N'-loweralkanoylpiperazino-lower alkyl, unsubstituted or lower alkylatedmorpholino-lower alkyl, such as morpholino-lower alkyl ordimethylmorpholino-lower alkyl, or optionally S-oxidisedthiomorpholino-lower alkyl, such as thiomorpholino-lower alkyl,S,S-dioxothiomorpholino-lower alkyl, carboxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- orN,N-di-lower alkylcarbamoyl-lower alkyl, dicarboxy-lower alkyl, di-loweralkoxycarbonyl-lower alkyl, dicarbamoyl-lower alkyl, di-(N-mono- orN,N-di-lower alkylcarbamoyl)-lower alkyl, carboxy-(hydroxy)-lower alkyl,lower alkoxy-carbonyl-(hydroxy)-lower alkyl or carbamoyl-(hydroxy)-loweralkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl,sulfamoyl-lower alkyl, lower alkyl-sulfamoyl-lower alkyl, di-loweralkylsulfamoyl-lower alkyl, thiocarbamoyl-lower alkyl, loweralkylthiocarbamoyl-lower alkyl, di-lower alkylthiocarbamoyl-lower alkyl,pyrrolidinyl, imidazolyl, benzimidazolyl, oxadiazolyl, pyridyl,oxopiperidinyl, quinolinyl, unsubstituted or N-lower alkanoylatedpiperidyl or pyrrolidinyl, imidazolyl-lower alkyl, benzimidazolyl-loweralkyl, oxadiazolyl-lower alkyl, pyridyl-lower alkyl, unsubstituted orN-lower alkanoylated piperidyl-lower alkyl or pyrrolidinyl-lower alkyl,oxopiperidinyl-lower alkyl, quinolinyl-lower alkyl,morpholinocarbonyl-lower alkyl or unsubstituted or N-lower alkanoylatedpiperidyl-lower alkyl,or a salt thereof.
 3. A compound according toclaim 1 of formula I whereinR₁ is hydrogen, R₂ is lower alkyl, loweralkoxy-lower alkyl, lower alkoxy-lower alkoxy, lower alkoxy-toweralkoxy-lower alkyl; phenyl-lower alkoxy that is unsubstituted orsubstituted by bower alkyl, lower alkoxy, hydroxy, halogen, nitro and/orby amino; optionally N-oxidised pyridyl-lower alkoxy, loweralkylthio-lower alkoxy, lower alkanesulfonyl-lower alkoxy, loweralkanoyl-lower alkoxy, optionally N-oxidised pyridyl-lower alkoxy,cyano-lower alkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-loweralkoxy, carbamoyl-lower alkoxy, lower alkylcarbamoyl-lower alkoxy ordi-lower alkylcarbamoyl-lower alkoxy, R₃ is hydrogen, lower alkyl,hydroxy, lower alkoxy or polyhalo-lower alkoxy, R₄ is hydrogen ortogether with R₃ is lower alkylidenedioxy, X is methylene, R₅ is loweralkyl or cycloalkyl. R₆ is amine, lower alkylamino, di-lower alkylaminoor lower alkanoylamino, R₇ is lower alkyl, and R₈ is lower alkyl,hydroxy-lower alkyl, lower alkanoyl-lower alkyl, lower alkoxy-loweralkyl, lower alkenyloxy-lower alkyl, amino-lower alkyl, loweralkanoyl-amino-lower alkyl, such as 2-(C₁ -C₄alkanoylamino)-2-methyl-propyl, such as 2-acetylamino-2-methyl-propyl or2-formylamino-2-methyl-propyl, N-mono- or N,N-di-lower alkylamino-loweralkyl, piperidino-lower alkyl, hydroxypiperidino-lower alkyl, loweralkoxypiperidino-lower alkyl, morpholino-lower alkyl,dimethylmorpholino-lower alkyl, thiomorpholino-lower alkyl.S,S-dioxothiomorpholino-lower alkyl, Carboxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- orN,N-di-lower alkylcarbamoyl-lower alkyl, carboxy-(hydroxy)-lower alkyl,lower alkoxycarbonyl-(hydroxy)-lower alkyl, carbamoyl-(hydroxy)-loweralkyl, 5- or 6-membered carboxycycloalkyl-lower alkyl, 5- or 6-memberedlower alkoxycarbonylcycloalkyl-lower alkyl. 5- or 6-memberedcarbamoylcycloalkyl-lower alkyl, 5- or 6-membered N-mono- or N,N-di-lower alkylcarbamoylcycloalkyl-lower alkyl, cyano-lower alkyl,lower alkanesulfonyl-lower alkyl, sulfamoyl-lower alkyl, loweralkylsulfamoyl-lower alkyl or di-lower alkylsulfamoyl-lower alkyl,imidazolyl-lower alkyl, oxopyrrolidinyl-lower alkyl,benzimidazolyl-lower alkyl, oxadiazolyl-lower alkyl, pyridyl-loweralkyl, oxopiperidinyl-lower alkyl or quinolinyl-lower alkyl,piperidin-4-yl-lower alkyl or 1-C₁ -C₇ -loweralkanoylpiperidin-4-yl-lower alkyl,or a salt thereof.
 4. A compoundaccording to claim I of formula I whereinR₁ and R4 are hydrogen. R₂ isC₁ -C₄ alkoxy-C₁ -C₄ alkoxy or C₁ -C₄ alkoxy-C₁ -C₄ alkyl, R₃ is C₁ -C₄alkyl or C₁ -C₄ alkoxy, R₆ is amino, X is methylene, R₅ and R7 arebranched C₁ -C₄ alkyl, and R₈ is carbamoyl-C₁ -C₄ alkyl, N-C₁ -C₄alkylcarbamoyl-C₁ -C₄ alkyl, N,N-di-C₁ -C₄ alkyl-carbamoyl-C₁ -C₄ alkyl,morpholino-C₁ -C₄ alkyl, thiomorpholino-C₁ -C₄ alkyl, 4-(1-C₁ -C₄alkanoylpiperidyl)-C₁ -C₄ alkyl or 2-oxopyrrolidinyl-C₁ -C₄ alkyl, or asalt thereof.
 5. A compound according to claim 1 of formula I wherein atleast one asymmetric carbon atom of the main chain has thestereochemical configuration shown in formula Ia ##STR40## each of thevariables being as defined in claim 1, or a pharmaceutically acceptablesalt thereof.
 6. A compound according to claim 1 selected from the groupconsisting of2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide;2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-ethyl-8-(p-tert-butyl-phenyl)-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-methyl-8-(4-biphenyl-octanoic acid(N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amine-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide; 2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-hydroxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-ethoxycarbonylmethoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-allyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxycarbonyl-allyloxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxycarbonyl-methoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-carbamoyl-methoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-2-yl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-4-yl-methoxy)-4-tert-butyl-phenyl]-octanoic acid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(N-oxido-pyrid-2-yl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide;2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxycarbonylallyl-oxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R. S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxycarbonyl-propyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide;2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylthio-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylsulfonyl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(carboxy-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3,3-dimethyl-2-oxo-butyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-nitrobenzyloxy)4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-aminobenzyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-chloro-2(Rhydroxypropyloxy)-4-tert-butyl-phenyl]-octanoic acid (N-butyl)amide;2(R,S]-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylthio-2(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylsulfonyl-(S,R)-hydroxypropyloxy)-4-tert-butyl-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylsulfonyl-methoxy)-4-tert-butyl-phenyl]-octanoicacid (N-3-morpholino-propyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-methoxycarbonyl-methoxy-phenyl)-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methoxycarbonyl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(N-methyl-carbamoyl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methylsulfonyl-propyloxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylsulfonyl-methoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-methoxy-propyloxy)-4-methoxy-phenyl]-octanoic acid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-methoxy-ethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-hydroxy-propyloxy)-4-methoxy-phenyl]-octanoic acid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(carbamoylmethoxy )-4-methoxy-phenyl]-octanoic acid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-cyanomethoxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(4-methoxy-butoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(2-ethoxy-ethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-{3-[2-(2-methoxy-ethoxy)-ethoxy]-4-methoxy-phenyl}-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-pentyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(3-ethoxy-propyloxy)-4methoxy-phenyl]-octanoicacid (N-butyl)amide;2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(pyrid-4-ylmethoxy)-4-methoxy-phenyl]-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-ethoxycarbonyl-methoxy-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide; 2(R, S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(2-ethoxycarbonyl-4-tert-butyl-phenyl)-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-hydroxypropyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-isopropyl-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-tert-butyl-3-(3-methoxy-propyl-oxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-methylsulfonyl-propyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid (N-2-morpholinoethyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-methylsulfonyl-propyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3,4-di(3-hydroxypropyloxy)-phenyl]-octanoicacid (N-2-morpholinoethyl)amide; 5(S)-amino-4(S)-hydroxy-2(S).7(S)-diisopropyl-8-[3,4-d i(3-hydroxypropyloxy)-phenyl]-octanoic acid[N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide;5(S]-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-N-methylcarbamoyl-propyl)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-2-morpholinoethyl)amide; 5(S)-amino-4(S)-hydroxy-2(S).7(S)-diisopropyl-8-[4-(2-morpholinoethoxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide;[5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxypropyloxy)-4,5-ethylenedioxy-phenyl]-octanoic acid (N-2-morpholinoethyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxypropyloxy)-4,5-ethylenedioxy-phenyl]-octanoic acid[N-(2-carbamoyl-2.2-dimethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxy-propyloxy)-4,5-methylenedioxy-phenyl]-octanoicacid (N-2-morpholinoethyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[3-(3-methoxypropyloxy)-4,5-methylenedioxy-phenyl]-octanoicacid [N-(2-carbamoyl-2.2-dimethyl-ethyl)]amide;]5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-ethylene-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propoxy )-phenyl]-octanoic acid[N-(3(S)-2-oxo-pyrrolidin-3-yl-methyl)]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(4-methoxy-but-2-eneoxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-hydroxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-H-benzyloxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[3,4-di(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(2,2,2-trifluoroethoxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-hydroxy-propyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(2-amino-ethoxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(5-amino-pentyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-amino-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-N,N-dimethylamino-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-{4-[4-N-(trifluoromethane-sulfonylaminobutyloxy)-3-(3-methoxypropyloxy)-phenyl]}-octanoicacid (N-butyl)-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-carboxymethoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-ethoxycarbonyl-propyloxy)-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(3-carboxy-propyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-methoxycarbonylbutyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-(4-carboxy-butyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxymethoxy-ethyl)-phenyl]-octanoicacid (N-butyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-hydroxypropyloxy)-3-( methoxypropyloxy)-phenyl]-octanoic acidN-(2-morpholinoethyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(4-hydroxypiperidin-1-yl)ethyl]amide dihydrochloride;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(trans-2,6-dimethyl-morpholino )ethyl]amide; 5(S)-am ino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-mepropyloxy)-phenyl]-octanoic acidN-[2-(cis-2,6-dimethyl-morpholino)ethyl]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(2-piperidinoethyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(4-methoxypiperidino )-ethyl]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(2-thiomorpholinoethyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-hydroxypropyl)]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4-acetoxybutyl)]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-cyanopropyl)]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-methoxypropyl)]amide; 5(S)-amno-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-acetylamino-ethyl)]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(2-pyridyl)-ethyl]}amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(N-oxomorpholino)ethyl]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[3-(tert-butylsulfonyl)-propyl]}amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[3-(ethylsulfonyl)-propyl]}-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(ethylsulfonyl)-ethyl]}-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(N-butylsulfonyl)-ethyl]}-amide;[(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylsulfonylamino)-ethyl]}-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[3-(1H-tetrazol-5-yl)-propyl]}-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[3-(1H-imidazol-5-yl)-propyl]}-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[3-(3-methyl-1,2,4-oxadiazol-5-yl)-propyl]}-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-aminopropyl)]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-[2-dimethylamino-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(2-morpholinoethyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(3-morpholinopropyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(1,1-dioxothiomorpholino)ethyl]amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(2-ethoxycarbonylethyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carboxy-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-methoxycarbonyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3-carboxypropyl)]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoylethyl)]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4-carbamoylbutyl)]-amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-{3-[N-(2-methoxyethyl)carbamoyl]propyl}amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid N-(4-morpholino-4-oxo-butyl)amide;5(S)-amino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-(1,1 -dimethyl-2-morpholino-ethyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[1 (R, S)-methyl-2-morpholino-ethyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(1 -carbamoyl-1 -methyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(I-carbamoyl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(2-carbamoyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(N-methyl-carbamoyl)ethyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid N-(3-morpholino-3-oxo-propyl)amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(N, N-dimethyl-carbamoyl)-1 (R, S)-methyl-ethyl]}-amide;(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1 (R)-isopropyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(N-methylcarbamoyl)-1(R)-isopropyl-ethyl]}-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(N,N-dimethylcarbamoyl)-I (R)-isopropyl-ethyl]}-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-2-hydroxy-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(,3-methoxy-propyloxy)-phenyl]-octanoic acid[N-(1(S),2-dicarbamoyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(1(S) ,3-dicarbamoyl-propyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-propyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-2(S)-methyl-butyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2(R, S )-carbamoyl-2(R, S )-methyl-ethyl]-amide;5(S)-amino4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(2-carbamoyl-1(S)-methyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carbamoyl-1 (R)-methyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2(S)-carbamoyl-2(S)-methylethyl]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid{N-[2(S)-(N-methyl-carbamoyl)-2(S)-methyl-ethyl]}-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carboxy-2,2-dimethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-carboxy-2,2-diethyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[(1-carboxy-cyclopentyl)-methyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid {N-[2-(1 H-tetrazol-5-yl)-ethyl]}-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[1(S)-(5-oxopyrrolidin-2-yl)methyl]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[1 (R)-(5-oxopyrrolidin-2-yl)methyl]-amide;5(S)-amine-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[N-(morpholin-4-yl)carbamoyl-methyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(1(S)-carbamoyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-{1(S)-[(N-methyl)-carbamoyl]-ethyl}-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid N-{1(S)-[(N,N-dimethyl)-carbamoyl]-ethyl}-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-{1(S)-N-[(morpholin-4-yl)-carbamoyl]-ethyl}amide;5(S)-amino-4(S)-hydroxy-2(S),7 (,S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acidN-[1(S)-carbamoylbutyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[1(S)-carbamoyl-2-methyl-propyl]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[1(S)-(N-methylcarbamoyl)-2-methyl-propyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[1(S)-(N,N-dimethylcarbamoyl)-2-methyl-propyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-{1(S)-[N-(morpholin-4-yl)carbamoyl]-2-methyl-propyl}amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(N-methylsulfonylamino)ethyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-{2-[N-(morpholin-4-yl)-sulfonyl]ethyl}amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[(N-acetyl-piperidin-4-yl)methyl]amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-butyl)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethylethyl)amide;5(S),amino,4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid N-[2-(N,N-dimethylcarbamoyl)ethyl]amide or5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxybutylphenyl]-octanoic acid N-(2-morpholinoethyl)amide,or in each case a saltthereof,
 7. A compound according to claim 1 which is selected from thegroup consisting of5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid[N-(3(R)-2-oxo-pyrrolidin-3-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(S)-2-oxo-piperidin-3-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(R)-2-oxo-piperidin-3-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyl-oxy)-phenyl]-octanoicacid [N-(3-carbamoyl-3,3-dimethyl-propyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-butyl)phenyl]-octanoicacid [N-(5(S)-2-pyrrolidinon-5-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-butyl)-phenyl]-octanoicacid [N-(5(R)-2-pyrrolidinon-5-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(6(S)-2-oxo-piperidin-6-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(6(R)-2-oxo-piperidin-6-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-thiazol-2-yl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4(S)-2-oxazolidinon-4-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4(R)-2-oxazolidinon-4-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(S)-2.5-dioxo-pyrrolidin-3-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(3(R)-2.5-dioxo-pyrrolidin-3-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(2,6-dioxo-piperidin-4-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4(S)-2-oxothiazolidin-4-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4(R)-2-oxothiazolidin-4-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(tetrahydro-2-pyrimidon-5-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid [N-(N-acetyl-2-amino-2-methyl-propyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(N-formyl-2-amino-2-methyl-propyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(4-acetyl-piperazinyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2,4-imidazolinedion-5-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-butyl)phenyl]-octanoic acid [N-(2-hydroxy-pyridin-6-yl-methyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2,2-dimethyl-2-sulfamoyl-ethyl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2,2-dimethyl-2-(N,N-dimethyl)-sulfamoyl-ethyl)]-amidehydrochloride;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(2-oxo-piperidin-3(R)-yl)]-amide;5(S]-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(2-oxo-piperidin-3(S)-yl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(2-oxo-piperidin-4-yl)]-amide;5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoicacid [N-(N-acetyl-piperidin-4-yl)]-amide or 5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(4-methoxy-but-1en-yl)-phenyl]-octanoic acid[N-(2-carbamoyl-2,2-dimethyl-ethyl)]-amideor in each case a saltthereof.
 8. A pharmaceutical composition comprising as pharmaceuticalactive ingredient a compound according to claim 1 in free form or inpharmaceutically acceptable salt form, together with one or morecustomary pharmaceutical excipient(s).
 9. A method of treatinghypertension, congestive heart failure, cardiac hypertrophy, cardiacfibrosis, cardiomyopathy postinfarction, nephropathy, vasculopathy,neuropathy, restenosis following angioplasty, raised intra-ocularpressure, glaucoma, abnormal vascular growth, hyperaldosteronism oranxiety states, characterized in that a therapeutically effective amountof a compound according to claim 1 in the free form or in the form of apharmaceutically acceptable salt is administered to a warm-bloodedorganism in need of such treatment.
 10. A compound according to claim 1being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid morpholinopropyl)amide or a salt thereof.
 11. A compound accordingto claim 1 being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid morpholinoethyl)amide or a salt thereof.
 12. A compound accordingto claim 1 being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2-(N-methyl-carbamoyl)-1 (R, S)-methyl-ethyl]}-amide or a saltthereof.
 13. A compound according to claim 1 being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(3-carbamoylpropyl)amide or a salt thereof.
 14. A compoundaccording to claim 1 being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[2(R)-(N-methyl-carbamoyl)-2(R)-methyl-ethyl]}-amide or a saltthereof.
 15. A compound according to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-thiomorpholinoethyl)amide or a salt thereof.
 16. A compoundaccording to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N, N-dimethyl-carbamoyl)ethyl]amide or a salt thereof.
 17. Acompound according to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-1(R,S)-methyl-ethyl)amide or a salt thereof.
 18. Acompound according to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R)-carbamoyl-2(R)-methyl-ethyl]-amide or a salt thereof.
 19. Acompound according to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)amide or a salt thereof.
 20. Acompound according to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2-(N-acetyl)-piperidin-4-yl)ethyl]amide or a salt thereof.
 21. Acompound according to claim 1 being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid {N-[(N,N-dimethyl)-carbamoyl-methyl]]-amide or a salt thereof. 22.A compound according to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-[2(R, S)-(N-methylcarbamoyl)-2(R,S)-methyl-ethyl]-amide or a saltthereof.
 23. A compound according to claim I being5(S)-Amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoicacid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide or a salt thereof.
 24. Acompound according to claim 1 being5(S)-Amino-2(S),7(S)-diisopropyl-4(S)-hydroxy-8-[4-tert-butyl-3-(3-methoxypropoxy)-phenyl]-octanoicacid [N-2-(morpholin-4-yl)-ethyl]-amide or a salt thereof.